Anti-respiratory syncytial virus antibodies, and methods of their generation and use

ABSTRACT

Anti-RSV antibodies with neutralizing potency against RSV subtype A and RSV subtype B are provided, as well as methods for their identification, isolation, generation, and methods for their preparation and use are provided.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. Provisional Patent Application No. 62/411,508, filed Oct. 21, 2016, the entire contents of which are incorporated herein by reference.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Oct. 20, 2017, is named “2009186_0218_SL.TXT” and is 1,019,600 bytes in size.

FIELD OF THE INVENTION

The invention relates, inter alia, to anti-Respiratory Syncytial Virus (RSV) antibodies and functional fragments thereof, nucleic acid sequences encoding such antibodies and methods and reagents for their preparation and use.

BACKGROUND OF THE INVENTION

All references cited herein, including without limitation patents, patent applications, and non-patent references and publications referenced throughout are hereby expressly incorporated by reference in their entireties for all purposes.

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in young children and the elderly, is the leading cause of infant hospitalization in the United States and accounts for an estimated 64 million infections and 160,000 deaths world-wide each year. However, despite decades of research, the development of a safe and effective vaccines or therapeutic and/or prophylactic antibodies against RSV has remained elusive, highlighting the need for novel strategies that induce or provide protective immune responses. (1-3). Indeed, to date there are currently no approved RSV vaccines, and passive prophylaxis with the monoclonal antibody palivizumab (marketed as Synagis®) is restricted to high-risk infants in part due to its modest efficacy.

Certain populations of children are at risk for developing an RSV infection and these include preterm infants (Hall et al., 1979, New Engl. J. Med. 300:393-396), children with congenital malformations of the airway, children with bronchopulmonary dysplasia (Groothuis et al., 1988, Pediatrics 82:199-203), children with congenital heart disease (MacDonald et al., New Engl. J. Med. 307:397-400), and children with congenital or acquired immunodeficiency (Ogra et al., 1988, Pediatr. Infect. Dis. J. 7:246-249; and Pohl et al., 1992, J. Infect. Dis. 165:166-169), and cystic fibrosis (Abman et al., 1988, J. Pediatr. 1 13:826-830).

RSV can infect the adult population as well. In this population, RSV causes primarily an upper respiratory tract disease, although elderly patients may be at greater risk for a serious infection and pneumonia (Evans, A. S., eds., 1989, Viral Infections of Humans. Epidemiology and Control, 3^(rd) ed., Plenum Medical Book, New York at pages 525-544), as well as adults who are immunosuppressed, particularly bone marrow transplant patients (Hertz et al., 1989, Medicine 68:269-281). Other at risk patients include those suffering from congestive heart failure and those suffering from chronic obstructive pulmonary disease (i.e. COPD). There have also been reports of epidemics among nursing home patients and institutionalized young adults (Falsey, A. R., 1991 , Infect. Control Hosp. Epidemiol. 12:602-608; and Garvie et al., 1980, Br. Med. J. 281 :1253-1254).

While treatment options for established RSV disease are limited, more severe forms of the disease of the lower respiratory tract often require considerable supportive care, including administration of humidified oxygen and respiratory assistance (Fields et al., eds, 1990, Fields Virology, 2^(nd) ed., Vol. 1, Raven Press, New York at pages 1045-1072).

Similar to other pneumoviruses, RSV expresses two major surface glycoproteins: the fusion protein (F) and the attachment protein (G). Although both have been shown to induce protective neutralizing antibody responses, F is less genetically variable than G, is absolutely required for infection, and is the target for the majority of neutralizing activity in human serum (4-8). RSV F is also the target of the monoclonal antibody palivizumab, which is used to passively protect high-risk infants from severe disease (9). Consequently, the RSV F protein is considered to be a highly attractive target for vaccines and antibody-based therapies.

The mature RSV F glycoprotein initially exists in a metastable prefusion conformation (preF) (10), before undergoing a conformational change that leads to insertion of the hydrophobic fusion peptide into the host-cell membrane. Subsequent refolding of F into a stable, elongated postfusion conformation (postF) (11, 12) results in fusion of the viral and host-cell membranes. Due to its inherent instability, the preF protein has the propensity to prematurely trigger into postF, both in solution and on the viral surface (13). Recently, stabilization of preF has been achieved by protein engineering (14, 15), and stabilized preF has been shown to induce higher titers of neutralizing antibodies than postF in animal models (15).

Despite the importance of neutralizing antibodies in protection against severe RSV disease, our understanding of the human antibody response to RSV has been limited to studies of human sera and a small number of RSV-specific human monoclonal antibodies (16-19). The epitopes recognized by these human antibodies, as well as several murine antibodies, have defined at least four ‘antigenic sites’ on RSV F (1, 10, 16, 18-20) (see also, e.g, Table 1). Three of these sites—I, II, and IV—are present on both pre- and postF, whereas antigenic site Ø exists exclusively on preF. Additional preF-specific epitopes have been defined by antibodies MPE8 (17) and AM14 (21). Although serum mapping studies have shown that site Ø-directed antibodies are responsible for a large proportion of the neutralizing antibody response in most individuals (8), there are additional antibody specificities that contribute to serum neutralizing activity that remain to be defined. In addition, it was heretofore unknown whether certain antibody sequence features are required for recognition of certain neutralizing sites, as observed for other viral targets (22-25). Accordingly, understanding the relationship between neutralization potency and epitope specificity would be advantageous in the selection and/or design of vaccine antigens, as well as therapeutic and/or prophylactic antibodies, which induce potent neutralizing responses to RSV.

While treatment options for established RSV disease are limited, more severe forms of the disease of the lower respiratory tract often require considerable supportive care, including administration of humidified oxygen and respiratory assistance (Fields et al., eds, 1990, Fields Virology, 2^(nd) ed., Vol. 1 , Raven Press, New York at pages 1045-1072).

Ribavirin, which is the only drug approved for treatment of infection, has been shown to be effective in the treatment of pneumonia and bronchiolitis associated with RSV infection, and has been shown to modify the course of severe RSV disease in immunocompetent children (Smith et al., 1991, New Engl. J. Med. 325:24-29). The use of ribavirin is limited due to concerns surrounding its potential risk to pregnant women who may be exposed to the aerosolized drug while it is being administered in a hospital environment.

Similarly, while a vaccine may be useful, no commercially available vaccine has been developed to date. Several vaccine candidates have been abandoned and others are under development (Murphy et al., 1994, Virus Res. 32: 13-36). The development of a vaccine has proven to be problematic. In particular, immunization would be required in the immediate neonatal period since the peak incidence of lower respiratory tract disease occurs at 2-5 months of age. However, it is known that the neonatal immune response is immature at that time. Plus, the infant at that point in time still has high titers of maternally acquired RSV antibody, which might reduce vaccine immunogenicity (Murphy et al., 1988, J. Virol. 62:3907-3910; and Murphy et al., 1991, Vaccine 9:185-189).

Currently, the only approved approach to prophylaxis of RSV disease is passive immunization. For example, the humanized antibody, palivizumab (SYNAGIS®), which is specific for an epitope on the F protein, is approved for intramuscular administration to pediatric patients for prevention of serious lower respiratory tract disease caused by RSV at recommended monthly doses of 15 mg/kg of body weight throughout the RSV season (November through April in the northern hemisphere). SYNAGIS® is a composite of human (95%) and murine (5%) antibody sequences. (Johnson et al., (1997), J. Infect. Diseases 176:1215-1224 and U.S. Pat. No. 5,824,307).

Although SYNAGIS® has been successfully used for the prevention of RSV infection in pediatric patients, multiple intramuscular doses of 15 mg/kg of SYNAGIS® are required to achieve a prophylactic effect. The necessity for the administration of multiple intramuscular doses of antibody requires repeated visits to the doctor's office, which is not only inconvenient for the patient but can also result in missed doses.

Efforts were made to improve on the therapeutic profile of an anti-RSV-F antibody, and this lead to the identification and development of motavizumab, also referred to as NUMAX™. However, clinical testing revealed that certain of the patients being administered motavizumab were having severe hypersensitivity reactions. Further development of this humanized anti-RSV-F antibody was then discontinued.

Other antibodies to RSV-F protein have been described and can be found in U.S. Pat. Nos. 6,656,467; 5,824,307, 7,786,273; 7,670,600; 7,083,784; 6818216; 7700735; 7553489; 7,323,172; 7,229,619; 7,425,618; 7,740,851 ; 7,658,921; 7,704,505; 7,635,568; 6,855,493; 6,565,849; 7,582,297; 7,208,162; 7,700,720; 6,413,771; 5,811,524; 6,537,809; 5,762,905; 7,070,786; 7,364,742; 7,879,329; 7,488,477; 7,867,497 ; 553,441 6,835,372; 7,482,024; 7,691,603; 8,562,996; 8,568,726; 9,447,173; US20100015596; WO2009088159A1; and WO2014159822. To date, none other than SYNAGIS® has been approved by a regulatory agency for use in preventing an RSV infection.

There remains a need for the provision of highly specific, high affinity, and highly potent neutralizing anti-RSV antibodies and antigen-binding fragments thereof with neutralize at least one, but preferably both, of subtype A and subtype B RSV viral strains, and which preferentially recognize PreF relative to PostF conformations of the F protein. There also remains a need for the provision of anti-RSV and anti-HMPV cross-neutralizing antibodies and antigen-binding fragments thereof.

SUMMARY OF THE INVENTION

Applicant has now discovered, isolated, and characterized, inter alia, an extensive panel of RSV F-specific monoclonal antibodies from the memory B cells of a healthy adult human donor and used these antibodies to comprehensively map the antigenic topology of RSV F. A large proportion of the RSV F-specific human antibody repertoire was advantageously comprised of antibodies with greatly enhanced specificity for the PreF conformation of the F protein (relative to the PostF form), many if not most of which exhibited remarkable potency in neutralization assays against one or both of RSV subtype A and RSV subtype B strains. Indeed, a large number of these antibodies display neutralization potencies that are multiple-fold greater—some 5- to 100-fold greater or more—to previous anti-RSV therapeutic antibodies, such as D25 and pavlizumamab thus serve as attractive therapeutic and/or prophylactic candidates for treating and/or preventing RSV infection and disease.

The most potent antibodies were found to target two distinct antigenic sites that are located near the apex of the preF trimer, providing strong support for the development of therapeutic and/or prophylactic antibodies targeting these antigenic sites, as well as preF-based vaccine candidates that preserve these antigenic sites. Furthermore, the neutralizing antibodies described and disclosed herein represent new opportunities for the prevention of severe RSV disease using passive immunoprophylaxis.

Given the role that the F protein plays in fusion of the virus with the cell and in cell to cell transmission of the virus, the antibodies described herein provide a method of inhibiting that process and as such, may be used for preventing infection of a patient exposed to, or at risk for acquiring an infection with RSV, or for treating and/or ameliorating one or more symptoms associated with RSV infection in a patient exposed to, or at risk for acquiring an infection with RSV, or suffering from infection with RSV. The antibodies and pharmaceutical compositions described herein may also be used to prevent or to treat an RSV infection in a patient who may experience a more severe form of the RSV infection due to an underlying or pre-existing medical condition. A patient who may benefit from treatment with an antibody and/or a pharmaceutical composition of the invention may be a pre-term infant, a full-term infant born during RSV season (approximately late fall (November) through early spring (April)) that is at risk because of other pre-existing or underlying medical conditions including congenital heart disease or chronic lung disease, a child greater than one year of age with or without an underlying medical condition, an institutionalized or hospitalized patient, or an elderly adult (>65 years of age) with or without an underlying medical condition, such as congestive heart failure (CHF), or chronic obstructive pulmonary disease (COPD). A patient who may benefit from such therapy may suffer from a medical condition resulting from a compromised pulmonary, cardiovascular, neuromuscular, or immune system. For example, the patient may suffer from an abnormality of the airway, or an airway malfunction, a chronic lung disease, a chronic or congenital heart disease, a neuromuscular disease that compromises the handling of respiratory secretions, or the patient may be immunosuppressed due to severe combined immunodeficiency disease or severe acquired immunodeficiency disease, or from any other underlying infectious disease or cancerous condition that results in immunosuppression, or the patient may be immunosuppressed due to treatment with an immunosuppressive drug (e.g. any drug used for treating a transplant patient) or radiation therapy. A patient who may benefit from the antibodies and/or pharmaceutical compositions of the invention may be a patient that suffers from chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), bronchopulmonary dysplasia, congestive heart failure (CHF), or congenital heart disease.

Because the inventive antibodies and antigen-binding fragments thereof are more effective at neutralization of RSV compared to known antibodies, lower doses of the antibodies or antibody fragments or pharmaceutical compositions of the invention could be used to achieve a greater level of protection against infection with RSV, and more effective treatment and/or amelioration of symptoms associated with an RSV infection. Accordingly, the use of lower doses of antibodies or fragments thereof which immunospecifically bind to RSV-F antigen and/or pharmaceutical compositions may result in fewer or less severe adverse events. Likewise, the use of more effective neutralizing antibodies may result in a diminished need for frequent administration of the antibodies or antibody fragments or pharmaceutical compositions than previously envisioned as necessary for the prevention of infection, or for virus neutralization, or for treatment or amelioration of one or more symptoms associated with an RSV infection. Symptoms of RSV infection may include a bluish skin color due to lack of oxygen (hypoxia), breathing difficulty (rapid breathing or shortness of breath), cough, croupy cough (“seal bark” cough), fever, nasal flaring, nasal congestion (stuffy nose), apnea, decreased appetite, dehydration, poor feeding, altered mental status, or wheezing.

Such antibodies or pharmaceutical compositions may be useful when administered prophylactically (prior to exposure to the virus and infection with the virus) to lessen the severity, or duration of a primary infection with RSV, or ameliorate at least one symptom associated with the infection. The antibodies or pharmaceutical compositions may be used alone or in conjunction with a second agent useful for treating an RSV infection. In certain embodiments, the antibodies or pharmaceutical compositions may be given therapeutically (after exposure to and infection with the virus) either alone, or in conjunction with a second agent to lessen the severity or duration of the primary infection, or to ameliorate at least one symptom associated with the infection. In certain embodiments, the antibodies or pharmaceutical compositions may be used prophylactically as stand-alone therapy to protect patients who are at risk for acquiring an infection with RSV, such as those described above. Any of these patient populations may benefit from treatment with the antibodies or pharmaceutical compositions of the invention, when given alone or in conjunction with a second agent, including for example, an anti-viral therapy, such as ribavirin, or other anti-viral vaccines.

The antibodies of the invention can be full-length (for example, an IgG1 or IgG4 antibody) or may comprise only an antigen-binding portion (for example, a Fab, F(ab′)₂ or scFv fragment), and may be modified to affect functionality, e.g., to eliminate residual effector functions (Reddy et al., (2000), J. Immunol. 164:1925-1933).

Accordingly, in certain embodiments are provided isolated antibodies or antigen-binding fragments thereof that specifically bind to Respiratory Syncytial Virus (RSV) F protein (F), wherein at least one, at least two, at least three, at least four, at least five, or at least six of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and CDRL3 amino acid sequence such antibodies or the antigen-binding fragments thereof are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; at least 100% and/or all percentages of identity in between; to at least one, at least two, at least three, at least four, at least five, or at least six of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences as disclosed in Table 6 of an antibody selected from Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; and wherein said antibody or the antigen-binding fragment thereof also has one or more of the following characteristics: a) the antibodies or antigen-binding fragments thereof cross-compete with said antibodies or antigen-binding fragments thereof for binding to RSV-F; b) the antibodies or antigen-binding fragments thereof display better binding affinity for the PreF form of RSV-F relative to the PostF form; c) the antibodies or antigen-binding fragments thereof display a clean or low polyreactivity profile; d) the antibodies or antigen-binding fragments thereof display neutralization activity toward RSV subtype A and RSV subtype B in vitro; e) the antibodies or antigen-binding fragments thereof display antigenic site specificity for RSV-F at Site Ø, Site I, Site II, Site III, Site IV, or Site V f) the antibodies or antigen-binding fragments thereof display antigenic site specificity for RSV-F Site Ø, Site V, or Site III relative to RSV-F Site I, Site II, or Site IV; g) at least a portion of the epitope with which the antibodies or antigen-binding fragments thereof interact comprises the α3 helix and β3/β4 hairpin of PreF; h) the antibodies or antigen-binding fragments thereof display an in vitro neutralization potency (IC₅₀) of between about 0.5 microgram/milliliter (ug/ml) to about 5 ug/ml; between about 0.05 ug/ml to about 0.5 ug/ml; or less than about 0.05 mg/ml; i) the binding affinities and/or epitopic specificities of the antibodies or antigen-binding fragments thereof for any one of the RSV-F variants designated as 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG in FIG. 7A is reduced or eliminated relative to the binding affinities and/or epitopic specificities of said antibodies or antigen-binding fragments thereof for the RSV-F or RSV-F DS-Cav1; j) the antibodies or antigen-binding fragments thereof display a cross-neutralization potency (IC₅₀) against human metapneumovirus (HMPV); k) the antibodies or antigen-binding fragments thereof do not complete with D25, MPE8, palivizumab, or motavizumab; or l) the antibodies or antigen-binding fragments thereof display at least about 2-fold; at least about 3-fold; at least about 4-fold; at least about 5-fold; at least about 6-fold; at least about 7-fold; at least about 8-fold; at least about 9-fold; at least about 10-fold; at least about 15-fold; at least about 20-fold; at least about 25-fold; at least about 30-fold; at least about 35-fold; at least about 40-fold; at least about 50-fold; at least about 55-fold; at least about 60-fold; at least about 70-fold; at least about 80-fold; at least about 90-fold; at least about 100-fold; greater than about 100-fold; and folds in between any of the foregoing; greater neutralization potency (IC50) than D25 and/or palivizumab.

In certain other embodiments, the isolated antibodies or antigen-binding fragments thereof comprise: at least two; at least three; at least 4; at least 5; at least 6; at least 7; at least 8; at least 9; at least 10; at least 11; or at least 12; of characteristics a) through 1) above.

In certain other embodiments, the isolated antibodies or antigen-binding fragments thereof comprise: a) the CDRH3 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; b) the CDRH2 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; c) the CDRH1 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; d) the CDRL3 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; e) the CDRL2 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; f) the CDRL1 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; or g) any combination of two or more of a), b), c), d), e), and f).

In certain other embodiments, the isolated antibodies or antigen-binding fragments thereof comprise: a) a heavy chain (HC) amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; and/or b) a light chain (LC) amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.

In certain other embodiments, the isolated antibodies or antigen-binding fragments thereof are selected from the group consisting of antibodies that are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to any one of the antibodies designated as Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.

In certain other embodiments, the isolated antibodies or antigen-binding fragments thereof are selected from the group consisting of the antibodies designated as Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.

In other embodiments are provided isolated nucleic acid sequences encoding antibodies, light and/or heavy chains thereof, antigen-binding fragments thereof, or light and/or heavy chains encoding such antigen-binding fragments according to any of the other embodiments disclosed herein.

In other embodiments are provided expression vectors comprising isolated nucleic acid sequences according to other embodiments disclosed herein.

In other embodiments are provided host cells transfected, transformed, or transduced with nucleic acid sequences or expression vectors according to other embodiments disclosed herein.

In other embodiments are provided pharmaceutical compositions comprising one or more of the isolated antibodies or antigen-binding fragments thereof according to other embodiments disclosed herein; and a pharmaceutically acceptable carrier and/or excipient.

In other embodiments are provided pharmaceutical compositions comprising a nucleic acid sequence of the invention, e.g., one or more nucleic acid sequences encoding at least one of a light or heavy chain of an antibody or both according other embodiments disclosed herein; or one or more expression vectors according to other embodiments disclosed herein; and a pharmaceutically acceptable carrier and/or excipient.

In other embodiments are provided transgenic organisms comprising nucleic acid sequences according to other embodiments disclosed herein; or expression vectors according to other embodiments disclosed herein.

In other embodiments are provided methods of treating or preventing a Respiratory Syncytial Virus (RSV) infection, or at least one symptom associated with RSV infection, comprising administering to a patient in need there of or suspected of being in need thereof: a) one or more antibodies or antigen-binding fragments thereof according to other embodiments disclosed herein; b) nucleic acid sequences according to other embodiments disclosed herein; an expression vector according to other embodiments disclosed herein; a host cell according to other embodiments disclosed herein; or e) a pharmaceutical composition according to other embodiments disclosed herein; such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.

In other embodiments are provided methods of treating or preventing either a Respiratory Syncytial Virus (RSV) infection and/or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof: a) one or more antibodies or antigen-binding fragments thereof according to other embodiments disclosed herein; b) a nucleic acid sequences according to other embodiments disclosed herein; c) an expression vector according to other embodiments disclosed herein; d)a host cell according to other embodiments disclosed herein; or e) a pharmaceutical composition according to other embodiments disclosed herein; such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity. In other embodiments are provided methods according to other embodiments wherein the one or more antibodies or antigen-binding fragments thereof of a) is selected from the group consisting of the antibodies designated as Antibody Number 340 as disclosed in Table 6.

In other embodiments are provided methods according to other embodiments wherein the method further comprises administering to the patient a second therapeutic agent.

In other embodiments are provided methods according to other embodiments, wherein the second therapeutic agent is selected group consisting of: an antiviral agent; a vaccine specific for RSV, a vaccine specific for influenza virus, or a vaccine specific for metapneumovirus (MPV); an siRNA specific for an RSV antigen or a metapneumovirus (MPV) antigen; a second antibody specific for an RSV antigen or a metapneumovirus (MPV) antigen; an anti-IL4R antibody, an antibody specific for an influenza virus antigen, an anti-RSV-G antibody and a NSAID.

In certain embodiments are provided pharmaceutical compositions comprising any one or more of the isolated antibodies or antigen-binding fragments thereof, or one or more nucleic acid sequences encoding at least one of a light chain or heavy chain of an antibody according to other embodiments disclosed herein or an antigen binding fragment thereof, and a pharmaceutically acceptable carrier and/or excipient.

In certain embodiments are provided pharmaceutical compositions according to other embodiments for use in preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof or suspected of being in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.

In certain embodiments are provided pharmaceutical compositions according to other embodiments for use in treating or preventing either a Respiratory Syncytial Virus (RSV) infection and/or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection and/or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.

In certain other embodiments are provided uses of the pharmaceutical compositions according to other embodiments in the manufacture of a medicament for preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration.

In certain other embodiments are provided uses of the pharmaceutical compositions according to other embodiments in the manufacture of a medicament for preventing either a Respiratory Syncytial Virus (RSV) infection and/or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection and/or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1F illustrate the anti-RSV repertoire cloning and sequence analysis of the identified and isolated antibodies. FIG. 1A: RSV F-specific B cell sorting. FACS plots show RSV F reactivity of IgG⁺ and IgA⁺ B cells from the healthy adult donor. B cells in quadrant 2 (Q2) were single cell sorted. FIG. 1B: Isotype analysis. Index sort plots show the percentage of RSV F-specific B cells that express IgG or IgA. FIG. 1C: Clonal lineage analysis. Each slice represents one clonal lineage; the size of the slice is proportional to the number of clones in the lineage. The total number of clones is shown in the center of the pie. Clonal lineages were assigned based on the following criteria: 1) matching of variable and joining gene segments; 2) identical CDR3 loop lengths; and 3) >80% homology in CDR3 nucleotide sequences. FIG. 1D: VH repertoire analysis. VH germline genes were considered to be enriched in the RSV repertoire if a given gene was found to be enriched by greater than 3-fold over non-RSV-specific repertoires (33). FIG. 1E: CDRH3 length distribution. FIG. 1F: Somatic hypermutation in VH (excluding CDRH3). Red bars indicate the average number of nucleotide substitutions. Each clonal lineage is only represented once in FIG. 1D and FIG. 1E. Data for non-RSV reactive IgGs were derived from published sequences obtained by high-throughput sequencing of re-arranged antibody variable gene repertoires from healthy individuals (33).

FIGS. 2A-2D illustrate the similar antibody preferences observed for conformational state and subtype of RSV F in the repertoire. FIG. 2A: IgG affinities for preF and postF are plotted as shown. FIG. 2B: Percentage of antibodies within the donor repertoire that recognized both conformations of F (green) or bind only to preF (blue) or postF (orange). FIG. 2C: Percentage of antibodies within the donor repertoire that bind specifically to subtype A (green), subtype B (blue), or both subtypes A and B (red). N.B., non-binder. IgG KDs were calculated for antibodies with BLI responses >0.1 nm. Antibodies with BLI responses <0.05 nm were designated as N.B. FIG. 2D: Polyreactivity analysis of anti-RSV antibodies. The polyreactivity of the isolated anti-RSV F antibodies was measured using a previously described assay (42, 43). Three panels of control antibodies were included for comparison: a group of 138 antibodies currently in clinical trials, 39 antibodies that have been approved for clinical use and 14 broadly neutralizing HIV antibodies.

FIGS. 3A-3G illustrate mapping and specificities of anti-RSV antibodies for antigenic sites spanning the surface of PreF and PostF. FIG. 3A: The previously determined structure of preF with one protomer shown as ribbons and with six antigenic sites rainbow colored from red to purple. FIG. 3B: The percentage of antibodies targeting each antigenic site is shown. FIG. 3C: Percentage of preF-specific antibodies targeting each antigenic site. FIG. 3D: Apparent antibody binding affinities for subtype A PreF antigenic sites. FIG. 3E: Apparent binding affinities for subtype A postF antigenic sites. FIG. 3F: Apparent antibody binding affinities for subtype B PreF antigenic sites. FIG. 3G. Apparent binding affinities for subtype B postF. Only antibodies with apparent binding affinities greater than 2 nM were included in this analysis, since antibodies with lower affinity could not be reliably mapped. Red bars show the median and the dotted grey line is at 2 nM. N.B., non-binder.

FIGS. 4A-4G illustrate neutralizing potencies of anti-RSV antibodies and correlation between potency and Pref vs. PostF specificity for each of RSV subtypes A and B. FIG. 4A: Neutralization IC₅₀s for the antibodies isolated from the donor repertoire. Data points are colored based on neutralization potency, according to the legend on the right. Red and blue dotted lines depict motavizumab and D25 IC₅₀s, respectively. FIG. 4B: Percentage of neutralizing antibodies in the donor repertoire against RSV subtype A or subtype B, stratified by potency as indicated in the legend in the right portion of the figure. FIG. 4C: Percentage of antibodies within the donor repertoire that neutralized both RSV subtypes A and B (red) or neutralized only RSV subtype A (green) or subtype B (blue). FIG. 4D: Apparent binding affinities for subtype A, preF and postF, plotted for each antibody (IgG KDs were calculated for antibodies with BLI responses >0.1 nm. Antibodies with BLI responses <0.05 nm were designated as N.B.) FIG. 4E: Neutralization IC₅₀s plotted for RSV subtype A preF-specific, postF-specific, and cross-reactive antibodies. (Red and blue dotted lines depict motavizumab and D25 IC₅₀s, respectively. Red bars depict median. N.B., non-binder; N.N., non-neutralizing). FIG. 4F: Apparent antibody binding affinities for subtype B, preF and postF. FIG. 4G: IC₅₀s plotted for RSV subtype B preF-specific, postF-specific and cross-reactive antibodies. (Black bar depicts median. N.B., non-binder; N.N., non-neutralizing.)

FIGS. 5A-5C illustrate that the most potent neutralizing antibodies bind with high affinity to preF and recognize antigenic sites Ø and V. FIG. 5A: apparent preF K_(D) plotted against neutralization IC₅₀ and colored according to antigenic site, as shown in the legend at right of FIG. 5C. FIG. 5B: apparent postF K_(D) plotted against neutralization IC₅₀ and colored as in FIG. 5A. FIG. 5C: antibodies grouped according to neutralization potency and colored by antigenic site as in legend at right. N.B., non-binder; N.N., non-neutralizing. IgG K_(D)s were calculated for antibodies with BLI responses >0.1 nm. Antibodies with BLI responses <0.05 nm were designated as N.B. Statistical significance was determined using an unpaired two-tailed t test. The Pearson's correlation coefficient, r, was calculated using Prism software version 7.0. Antibodies that failed to bind or neutralize were excluded from the statistical analysis due to the inability to accurately calculate midpoint concentrations.

FIGS. 6A-6C illustrate the nature and purification of pre- and postF sorting probes. FIG. 6A: Schematic of fluorescent prefusion RSV F probe shows one PE-conjugated streptavidin molecule bound by four avi-tagged trimeric prefusion F molecules. FIG. 6B: Coomassie-stained SDS-PAGE gel demonstrating the isolation of RSV F with a single AviTag per trimer using sequential Ni-NTA and Strep-Tactin purifications, as described in the Methods. FIG. 6C: Fluorescence size-exclusion chromatography (FSEC) trace of the tetrameric probes on a Superose 6 column. Positions of molecular weight standards are indicated with arrows.

FIGS. 7A-7C illustrate the generation and validation of preF patch panel mutants. FIG. 7A: Panel of RSV F variants used for epitope mapping. FIG. 7B: Prefusion RSV F shown as molecular surface with one protomer colored in white. The nine variants, each containing a patch of mutations, are uniquely colored according to the table in FIG. 7A. FIG. 7C: Binding of each IgG to fluorescently labeled beads coupled to each of the variants listed in FIG. 7A was measured using PE-conjugated anti-human Fc antibody on a FLEXMAP 3D flow cytometer (Luminex). Reduced binding of D25 and motavizumab to patches 1 and 5, respectively, is consistent with their structurally defined epitopes (10, 11). AM14 binding was reduced for both patch 3 and patch 9, due to its unique protomer-spanning epitope (21). This characteristic binding profile was used to assist in the classification of other possible quaternary-specific antibodies in the panel.

FIG. 8 illustrates the antigenic site V resides between the epitopes recognized by D25, MPE8 and motavizumab. Prefusion F is shown with one promoter as a cartoon colored according to antigenic site location and the other two protomers colored grey. D25 and motavizumab Fabs are shown in blue and pink, respectively. The MPE8 binding site is circled in black. Antigenic site V is located between the binding sites of D25 and MPE8 within one protomer, explaining the competition between site-V directed antibodies and these controls. Competition with motavizumab may occur across two adjacent protomers (left) or within one protomer (right), depending on the angle-of-approach of these site-V directed antibodies.

FIG. 9 illustrates percentage of anti-RSV antibodies demonstrating the indicated neutralizing activities of preF-specific, postF-specific, and cross-reactive antibodies. Antibodies were stratified according to neutralization potency and the percentage of antibodies in each group that were preF-specific (pink), postF-specific (white) or cross-reactive (orange) were plotted for subtype A (left panel) and subtype B (right panel).

FIGS. 10A-10C illustrate the relationship between subtype B neutralization and antigenic site specificity for anti-RSV antibodies. FIG. 10A: Subtype B preF affinity plotted against neutralization IC₅₀ for all antibodies and colored by antigenic site according to the color scheme depicted in FIG. 10C, right portion. FIG. 10B: PostF affinity plotted against IC₅₀ and colored as in FIG. 10A. FIG. 10C: Antibodies with preF affinities higher than 2 nM grouped according to neutralization potency and colored by antigenic site (right portion).

FIG. 11 illustrates in vitro neutralization of RSV A2 for specific anti-RSV antibodies. Inhibition of RSV-replication was measured in an ELISA based neutralization Assay using Hep-2 cells. Cells, mAbs and viruses were co-incubated for 4 days at 37° C., followed by quantification of viral proteins in infected cells using a polyclonal anti-RSV antibody. % inhibition was calculated relative to control cells infected with virus in absence of neutralizing antibody. Data are expressed as half-maximal inhibitory concentration that resulted in 50% reduction in virus replication (IC50) and represent the mean +/−SEM of two independent experiments. An isotype matched control mAb (*) was included in every experiment and did not exhibit virus neutralization.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the term “about,” when used in reference to a particular recited numerical value, means that the value may vary from the recited value by no more than 1%. For example, as used herein, the expression “about 100” includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

Definitions

“Respiratory Syncytial Virus-F protein”, also referred to as “RSV-F” or “RSV F” is a type I transmembrane surface protein, which has an N terminal cleaved signal peptide and a membrane anchor near the C terminus (Collins, P. L. et al., (1984), PNAS (USA) 81 :7683-7687). The RSV-F protein is synthesized as an inactive 67 KDa precursor denoted as F0 (Calder, L. J.; et al., Virology (2000), 277,122-131. The F0 protein is activated proteolytically in the Golgi complex by a furin-like protease at two sites, yielding two disulfide linked polypeptides, F2 and F1, from the N and C terminal, respectively. There is a 27 amino acid peptide released called “pep27”. There are furin cleavage sites (FCS) on either side of the pep27 (Collins, P. L.; Mottet, G. (1991), J. Gen. Virol., 72: 3095-3101 ; Sugrue, R. J, et al. (2001), J. Gen. Virol., 82, 1375-1386). The F2 subunit consists of the Heptad repeat C (HRC), while the F1 contains the fusion polypeptide (FP), heptad repeat A (HRA), domain I, domain II, heptad repeat B (HRB), transmembrane (TM) and cytoplasmic domain (CP) (See Sun, Z. et al. Viruses (2013), 5:21 1-225). The RSV-F protein plays a role in fusion of the virus particle to the cell membrane, and is expressed on the surface of infected cells, thus playing a role in cell to cell transmission of the virus and syncytia formation. The amino acid sequence of the RSV-F protein is provided in GenBank as accession number AAX23994.

A stabilized variant of the PreF trimeric conformation of RSV-F, termed “RSV-DS-Cav1”, or “DS-Cav1” disclosed in, inter alia, Stewart-Jones et al., PLos One, Vol. 10(6)):e0128779 and WO 2011/050168 was used in the identification, isolation, and characterization of the antibodies disclosed herein.

The term “laboratory strain” as used herein refers to a strain of RSV (subtype A or B) that has been passaged extensively in in vitro cell culture. A “laboratory strain” can acquire adaptive mutations that may affect their biological properties. A “clinical strain” as used herein refers to an RSV isolate (subtype A or B), which is obtained from an infected individual and which has been isolated and grown in tissue culture at low passage.

The term “effective dose 99” or “ED₉₉” refers to the dosage of an agent that produces a desired effect of 99% reduction of viral forming plaques relative to the isotype (negative) control. In the present invention, the ED₉₉ refers to the dosage of the anti-RSV-F antibodies that will neutralize the virus infection (e.g., reduce 99% of viral load) in vivo, as described in Example 5.

The term “IC₅₀” refers to the “half maximal inhibitory concentration”, which value measures the effectiveness of compound (e.g., anti-RSV-F antibody) inhibition towards a biological or biochemical utility. This quantitative measure indicates the quantity required for a particular inhibitor to inhibit a given biological process by half In certain embodiments, RSV virus neutralization potencies for anti-RSV and/or anti-RSV/anti-HMPV cross-neutralizing antibodies disclosed herein are expressed as neutralization IC₅₀ values.

“Palivizumab”, also referred to as “SYNAGIS®”, is a humanized anti-RSV-F antibody with heavy and light chain variable domains having the amino acid sequences as set forth in U.S. Pat. Nos. 7,635,568 and 5,824,307. This antibody, which immunospecifically binds to the RSV-F protein, is currently FDA-approved for the passive immunoprophylaxis of serious RSV disease in high-risk children and is administered intramuscularly at recommended monthly doses of 15 mg/kg of body weight throughout the RSV season (November through April in the northern hemisphere). SYNAGIS® is composed of 95% human and 5% murine antibody sequences. See also Johnson et al., (1997), J. Infect. Diseases 176:1215-1224.

“Motavizumab”, also referred to as “NUMAX™”, is an enhanced potency RSV-F-specific humanized monoclonal antibody derived by in vitro affinity maturation of the complementarity—determining regions of the heavy and light chains of palivizumab. For reference purposes, the amino acid sequence of the NUMAX™ antibody is disclosed in U.S Patent Publication 2003/0091584 and in U.S. Pat. No. 6,818,216 and in Wu et al., (2005) J. Mol. Bio. 350(1):126-144 and in Wu, et al. (2007) J. Mol. Biol. 368:652-665. It is also shown herein as SEQ ID NO: 359 for the heavy chain and as SEQ ID NO: 360 for the light chain of the antibody.

As used herein, the terms “treat,” “treatment” and “treating” refer to the reduction or amelioration of the progression, severity, and/or duration of an upper and/or lower respiratory tract RSV infection and/or human metapneumovirus (HMPV), otitis media, or a symptom or respiratory condition related thereto (such as asthma, wheezing, or a combination thereof) resulting from the administration of one or more therapies (including, but not limited to, the administration of one or more prophylactic or therapeutic agents). In certain embodiments, such terms refer to the reduction or inhibition of the replication of RSV and/or HMPV, the inhibition or reduction in the spread of RSV and/or HMPV to other tissues or subjects (e.g., the spread to the lower respiratory tract), the inhibition or reduction of infection of a cell with a RSV and/or HMPV, or the amelioration of one or more symptoms associated with an upper and/or lower respiratory tract RSV infection or otitis media.

As used herein, the terms “prevent,” “preventing,” and “prevention” refer to the prevention or inhibition of the development or onset of an upper and/or lower respiratory tract RSV and/or HMPV infection, otitis media or a respiratory condition related thereto in a subject, the prevention or inhibition of the progression of an upper respiratory tract RSV and/or HMPV infection to a lower respiratory tract RSV and/or HMPV infection, otitis media or a respiratory condition related thereto resulting from the administration of a therapy (e.g., a prophylactic or therapeutic agent), the prevention of a symptom of an upper and/or lower tract RSV and/or HMPV infection, otitis media or a respiratory condition related thereto, or the administration of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents). As used herein, the terms “ameliorate” and “alleviate” refer to a reduction or diminishment in the severity a condition or any symptoms thereof.

The term “antibody”, as used herein, is intended to refer to immunoglobulin molecules comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds (i.e., “full antibody molecules”), as well as multimers thereof (e.g. IgM) or antigen-binding fragments thereof. Each heavy chain (HC) is comprised of a heavy chain variable region (“HCVR” or “V_(H)”) and a heavy chain constant region (comprised of domains C_(H)1, C_(H)2 and C_(H)3). Each light chain (LC) is comprised of a light chain variable region (“LCVR or “V_(L)”) and a light chain constant region (C_(L)). The V_(H) and V_(L) regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). Each V_(H) and V_(L) is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR, CDR1, FR2, CDR2, FR3, CDR3, FR4. In certain embodiments of the invention, the FRs of the antibody (or antigen binding fragment thereof) may be identical to the human germline sequences, or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs. Accordingly, the CDRs in a heavy chain are designated “CHRH1”, “CDRH2”, and “CDRH3”, respectively, and the CDRs in a light chain are designated “CDRL1”, “CDRL2”, and “CDRL3”.

Substitution of one or more CDR residues or omission of one or more CDRs is also possible. Antibodies have been described in the scientific literature in which one or two CDRs can be dispensed with for binding. Padlan et al. (1995 FASEB J. 9:133-139) analyzed the contact regions between antibodies and their antigens, based on published crystal structures, and concluded that only about one fifth to one third of CDR residues actually contact the antigen. Padlan also found many antibodies in which one or two CDRs had no amino acids in contact with an antigen (see also, Vajdos et al. 2002 J Mol Biol 320:415-428).

CDR residues not contacting antigen can be identified based on previous studies (for example residues H60-H65 in CDRH2 are often not required), from regions of Kabat CDRs lying outside Chothia CDRs, by molecular modeling and/or empirically. If a CDR or residue(s) thereof is omitted, it is usually substituted with an amino acid occupying the corresponding position in another human antibody sequence or a consensus of such sequences. Positions for substitution within CDRs and amino acids to substitute can also be selected empirically.

The fully human monoclonal antibodies disclosed herein may comprise one or more amino acid substitutions, insertions and/or deletions in the framework and/or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. The present invention includes antibodies, and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and/or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein collectively as “germline mutations”). A person of ordinary skill in the art, starting with the heavy and light chain variable region sequences disclosed herein, can easily produce numerous antibodies and antigen-binding fragments which comprise one or more individual germline mutations or combinations thereof. In certain embodiments, all of the framework and/or CDR residues within the V_(H) and/or V_(L) domains are mutated back to the residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are mutated back to the original germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1, CDR2 or CDR3. In other embodiments, one or more of the framework and/or CDR residue(s) are mutated to the corresponding residue(s) of a different germline sequence (i.e., a germline sequence that is different from the germline sequence from which the antibody was originally derived). Furthermore, the antibodies of the present invention may contain any combination of two or more germline mutations within the framework and/or CDR regions, e.g., wherein certain individual residues are mutated to the corresponding residue of a particular germline sequence while certain other residues that differ from the original germline sequence are maintained or are mutated to the corresponding residue of a different germline sequence. Once obtained, antibodies and antigen-binding fragments that contain one or more germline mutations can be easily tested for one or more desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present invention.

The present invention also includes fully monoclonal antibodies comprising variants of any of the CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, the present invention includes antibodies having CDR amino acid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. conservative amino acid substitutions relative to any of the CDR amino acid sequences disclosed herein.

The term “human antibody”, as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human mAbs of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3.

However, the term “human antibody”, as used herein, is not intended to include mAbs in which CDR sequences derived from the germline of another mammalian species (e.g., mouse), have been grafted onto human FR sequences.

The term “humanized antibody” refers to human antibody in which one or more CDRs of such antibody have been replaced with one or more corresponding CDRs obtained a non-human derived (e.g., mouse, rat, rabbit, primate) antibody. Humanized antibodies may also include certain non-CDR sequences or residues derived from such non-human antibodies as well as the one or more non-human CDR sequence. Such antibodies may also be referred to as “chimeric antibodies”.

The term “recombinant” generally refers to any protein, polypeptide, or cell expressing a gene of interest that is produced by genetic engineering methods. The term “recombinant” as used with respect to a protein or polypeptide, means a polypeptide produced by expression of a recombinant polynucleotide. The proteins used in the immunogenic compositions of the invention may be isolated from a natural source or produced by genetic engineering methods.

The antibodies of the invention may, in some embodiments, be recombinant human antibodies. The term “recombinant human antibody”, as used herein, is intended to include all antibodies, including human or humanized antibodies, that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the V_(H) and V_(L) regions of the recombinant antibodies are sequences that, while derived from and related to human germline V_(H) and V_(L) sequences, may not naturally exist within the human antibody germline repertoire in vivo.

The term “specifically binds,” or “binds specifically to”, or the like, means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiologic conditions. Specific binding can be characterized by an equilibrium dissociation constant of at least about 1×10⁻⁶ M or less (e.g., a smaller K_(D) denotes a tighter binding). Methods for determining whether two molecules specifically bind are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. As described herein, antibodies have been identified by surface plasmon resonance, e.g., BIACORE™, biolayer interferometry measurements using, e.g., a ForteBio Octet HTX instrument (Pall Life Sciences), which bind specifically to RSV-F. Moreover, multi-specific antibodies that bind to RSV-F protein and one or more additional antigens, such as an antigen expressed by HMPV, or a bi-specific that binds to two different regions of RSV-F are nonetheless considered antibodies that “specifically bind”, as used herein. In certain embodiments, the antibodies disclosed herein display equilibrium dissociation constants (and hence specificities) of about 1×10−⁶ M; about 1×10−⁷ M; about 1×10−⁸ M; about 1×10−⁹ M; about 1×10⁻¹⁰ M; between about 1×10⁻⁶ M and about 1×10−⁷ M; between about 1×10−⁷M and about 1×10−⁸ M; between about 1×10−⁸ M and about 1×10−⁹ M; or between about 1×10−⁹ M and about 1×10−¹⁰ M.

The term “high affinity” antibody refers to those mAbs having a binding affinity to RSV-F and/or HMPV, expressed as K_(D), of at least 10−⁹ M; more preferably 10−¹⁰M, more preferably 10⁻¹¹M, more preferably 10⁻¹²M as measured by surface plasmon resonance, e.g., BIACORE™, biolayer interferometry measurements using, e.g., a ForteBio Octet HTX instrument (Pall Life Sciences), or solution-affinity ELISA.

By the term “slow off rate”, “Koff” or “kd” is meant an antibody that dissociates from RSV-F, with a rate constant of 1×10⁻³ s^(″1) or less, preferably 1×10⁻⁴ s^(″1) or less, as determined by surface plasmon resonance, e.g., BIACORE™ or a ForteBio Octet HTX instrument (Pall Life Sciences).

The terms “antigen-binding portion” of an antibody, “antigen-binding fragment” of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. In certain embodiments, the terms “antigen-binding portion” of an antibody, or “antibody fragment”, as used herein, refers to one or more fragments of an antibody that retains the ability to bind to RSV-F and/or HMPV.

An antibody fragment may include a Fab fragment, a F(ab′)₂fragment, a Fv fragment, a dAb fragment, a fragment containing a CDR, or an isolated CDR. Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and (optionally) constant domains. Such DNA is known and/or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and/or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.

Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab′)2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression “antigen-binding fragment,” as used herein.

An antigen-binding fragment of an antibody will typically comprise at least one variable domain. The variable domain may be of any size or amino acid composition and will generally comprise at least one CDR, which is adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a V_(H) domain associated with a V_(L) domain, the V_(H) and V_(L) domains may be situated relative to one another in any suitable arrangement. For example, the variable region may be dimeric and contain V_(H)-V_(H), V_(H)-V_(L) or V_(L)-V_(L) dimers. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric V_(H) or V_(L) domain.

In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting, exemplary configurations of variable and constant domains that may be found within an antigen-binding fragment of an antibody of the present invention include: (i) V_(H)-C_(H)1 ; (ii) V_(H)-C_(H)2; (iii) V_(H)-C_(H)3; (iv) V_(H)-C_(h)1-C_(h)2; (v) V_(H)-C_(h)1-C_(h)2-C_(h)3; (vi) V_(H)-C_(H)2-C_(H)3; (vii) V_(H)-C_(L); V_(L)-C_(H)1 ; (ix) V_(L)-C_(H)2; (x) V_(L)-C_(H)3; (xi) V_(L)-C_(H)1-C_(H)2; (xii) V_(L)-C_(H)1-C_(H)2-C_(H)3; (xiii) V_(L)-C_(H)2-C_(H)3; and (xiv) V_(L)-C_(L). In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region. A hinge region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, which result in a flexible or semi-flexible linkage between adjacent variable and/or constant domains in a single polypeptide molecule. Moreover, an antigen-binding fragment of an antibody of the present invention may comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with one another and/or with one or more monomeric V_(H) or V_(L) domain (e.g., by disulfide bond(s)).

As with full antibody molecules, antigen-binding fragments may be mono-specific or multi-specific (e.g., bi-specific). A multi-specific antigen-binding fragment of an antibody will typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multi-specific antibody format, including the exemplary bi-specific antibody formats disclosed herein, may be adapted for use in the context of an antigen-binding fragment of an antibody of the present invention using routine techniques available in the art.

The specific embodiments, antibody or antibody fragments of the invention may be conjugated to a therapeutic moiety (“immunoconjugate”), such as an antibiotic, a second anti-RSV-F antibody, an anti-HMPV antibody, a vaccine, or a toxoid, or any other therapeutic moiety useful for treating an RSV infection and/or an HMPV infection.

An “isolated antibody”, as used herein, is intended to refer to an antibody that is substantially free of other antibodies (Abs) having different antigenic specificities (e.g., an isolated antibody that specifically binds RSV-F and/or HMPV, or a fragment thereof, is substantially free of Abs that specifically bind antigens other than RSV-F and/or HMPV.

A “blocking antibody” or a “neutralizing antibody”, as used herein (or an “antibody that neutralizes RSV-F and/or HMPV activity”), is intended to refer to an antibody whose binding to RSV-F or to an HMPV antigen, as the case may be as disclosed herein, results in inhibition of at least one biological activity of RSV-F and/or HMPV. For example, an antibody of the invention may aid in blocking the fusion of RSV and/or HMPV to a host cell, or prevent syncytia formation, or prevent the primary disease caused by RSV and/or HMPV. Alternatively, an antibody of the invention may demonstrate the ability to ameliorate at least one symptom of the RSV infection and or HMPV infection. This inhibition of the biological activity of RSV-F and/or HMPV can be assessed by measuring one or more indicators of RSV-F and/or HMPV biological activity by one or more of several standard in vitro assays (such as a neutralization assay, as described herein) or in vivo assays known in the art (for example, animal models to look at protection from challenge with RSV and/or HMPV following administration of one or more of the antibodies described herein).

The term “surface plasmon resonance”, as used herein, refers to an optical phenomenon that allows for the analysis of real-time biomolecular interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIACORE™ system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.).

The term “K_(D)”, as used herein, is intended to refer to the equilibrium dissociation constant of a particular antibody-antigen interaction.

The term “epitope” refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different areas on an antigen and may have different biological effects. The term “epitope” also refers to a site on an antigen to which B and/or T cells respond. It also refers to a region of an antigen that is bound by an antibody. Epitopes may be defined as structural or functional. Functional epitopes are generally a subset of the structural epitopes and have those residues that directly contribute to the affinity of the interaction. Epitopes may also be conformational, that is, composed of non-linear amino acids. In certain embodiments, epitopes may include determinants that are chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, may have specific three-dimensional structural characteristics, and/or specific charge characteristics.

The term “substantial identity”, or “substantially identical,” when referring to a nucleic acid or fragment thereof, indicates that, when optimally aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 90%, and more preferably at least about 95%, 96%, 97%, 98% or 99% of the nucleotide bases, as measured by any well-known algorithm of sequence identity, such as FASTA, BLAST or GAP, as discussed below. Accordingly, nucleic acid sequences that display a certain percentage “identity” share that percentage identity, and/or are that percentage “identical” to one another. A nucleic acid molecule having substantial identity to a reference nucleic acid molecule may, in certain instances, encode a polypeptide having the same or substantially similar amino acid sequence as the polypeptide encoded by the reference nucleic acid molecule.

In certain embodiments, the disclosed antibody nucleic acid sequences are, e.g., at least 70% identical; at least 75% identical; at least 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99% identical; or 100% identical; and/or all percentages of identity in between; to other sequences and/or share such percentage identities with one another (or with certain subsets of the herein-disclosed antibody sequences).

As applied to polypeptides, the term “substantial identity” or “substantially identical” means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 90% sequence identity, even more preferably at least 95%, 98% or 99% sequence identity. Accordingly, amino acid sequences that display a certain percentage “identity” share that percentage identity, and/or are that percentage “identical” to one another. Accordingly, amino acid sequences that display a certain percentage “identity” share that percentage identity, and/or are that percentage “identical” to one another.

In certain embodiments, the disclosed antibody amino acid sequences are, e.g., at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to other sequences and/or share such percentage identities with one another (or with certain subsets of the herein-disclosed antibody sequences).

Preferably, residue positions, which are not identical, differ by conservative amino acid substitutions. A “conservative amino acid substitution” is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well known to those of skill in the art. (See, e.g., Pearson (1994) Methods Mol. Biol. 24: 307-331). Examples of groups of amino acids that have side chains with similar chemical properties include 1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; 2) aliphatic-hydroxyl side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, arginine, and histidine; 6) acidic side chains: aspartate and glutamate, and 7) sulfur-containing side chains: cysteine and methionine. Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine. Alternatively, a conservative replacement is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256: 1443 45. A “moderately conservative” replacement is any change having a nonnegative value in the PAM250 log-likelihood matrix.

Sequence similarity for polypeptides is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions. For instance, GCG software contains programs such as GAP and BESTFIT which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild type protein and a mutein thereof. See, e.g., GCG Version 6.1. Polypeptide sequences also can be compared using FASTA with default or recommended parameters; a program in GCG Version 6.1. FASTA {e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson (2000) supra). Another preferred algorithm when comparing a sequence of the invention to a database containing a large number of sequences from different organisms is the computer program BLAST, especially BLASTP or TBLASTN, using default parameters. (See, e.g., Altschul et al. (1990) J. Mol. Biol. 215: 403 410 and (1997) Nucleic Acids Res. 25:3389 402).

In certain embodiments, the antibody or antibody fragment for use in the method of the invention may be mono-specific, bi-specific, or multi-specific. Multi-specific antibodies may be specific for different epitopes of one target polypeptide or may contain antigen-binding domains specific for epitopes of more than one target polypeptide. An exemplary bi-specific antibody format that can be used in the context of the present invention involves the use of a first immunoglobulin (Ig) C_(H)3 domain and a second Ig C_(H)3 domain, wherein the first and second Ig C_(H)3 domains differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces binding of the bi-specific antibody to Protein A as compared to a bi-specific antibody lacking the amino acid difference. In one embodiment, the first Ig C_(H)3 domain binds Protein A and the second Ig C_(H)3 domain contains a mutation that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering; H435R by EU numbering). The second C_(H)3 may further comprise an Y96F modification (by IMGT; Y436F by EU). Further modifications that may be found within the second C_(H)3 include: D16E, L18M, N44S, K52N, V57M, and V82I (by IMGT; D356E, L358M, N384S, K392N, V397M, and V422I by EU) in the case of IgG1 mAbs; N44S, K52N, and V82I (IMGT; N384S, K392N, and V422I by EU) in the case of IgG2 mAbs; and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I by EU) in the case of IgG4 mAbs. Variations on the bi-specific antibody format described above are contemplated within the scope of the present invention.

By the phrase “therapeutically effective amount” is meant an amount that produces the desired effect for which it is administered. The exact amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

An “immunogenic composition” relates to a composition containing an antigen/immunogen, e.g., a microorganism, such as a virus or a bacterium, or a component thereof, a protein, a polypeptide, a fragment of a protein or polypeptide, a whole cell inactivated, subunit or attenuated virus, or a polysaccharide, or combination thereof, administered to stimulate the recipient's humoral and/or cellular immune systems to one or more of the antigens/immunogens present in the immunogenic composition. The immunogenic compositions of the present invention can be used to treat a human susceptible to RSV and/or HMPV infection or suspected of having or being susceptible to RSV and/or HMPV infection, by means of administering the immunogenic compositions via a systemic route. These administrations can include injection via the intramuscular (i.m.), intradermal (i.d.), intranasal or inhalation route, or subcutaneous (s.c.) routes; application by a patch or other transdermal delivery device. In one embodiment, the immunogenic composition may be used in the manufacture of a vaccine or in the elicitation of polyclonal or monoclonal antibodies that could be used to passively protect or treat a mammal.

The terms “vaccine” or “vaccine composition”, which are used interchangeably, refer to a composition comprising at least one immunogenic composition that induces an immune response in an animal.

In certain embodiments, a protein of interest comprises an antigen. The terms “antigen,” “immunogen,” “antigenic,” “immunogenic,” “antigenically active,” and “immunologically active” when made in reference to a molecule, refer to any substance that is capable of inducing a specific humoral and/or cell-mediated immune response. In one embodiment, the antigen comprises an epitope, as defined above.

“Immunologically protective amount”, as used herein, is an amount of an antigen effective to induce an immunogenic response in the recipient that is adequate to prevent or ameliorate signs or symptoms of disease, including adverse health effects or complications thereof. Either humoral immunity or cell-mediated immunity or both can be induced. The immunogenic response of an animal to a composition can be evaluated, e.g., indirectly through measurement of antibody titers, lymphocyte proliferation assays, or directly through monitoring signs and symptoms after challenge with the microorganism. The protective immunity conferred by an immunogenic composition or vaccine can be evaluated by measuring, e.g., reduction of shed of challenge organisms, reduction in clinical signs such as mortality, morbidity, temperature, and overall physical condition, health and performance of the subject. The immune response can comprise, without limitation, induction of cellular and/or humoral immunity. The amount of a composition or vaccine that is therapeutically effective can vary, depending on the particular organism used, or the condition of the animal being treated or vaccinated.

An “immune response”, or “immunological response” as used herein, in a subject refers to the development of a humoral immune response, a cellular-immune response, or a humoral and a cellular immune response to an antigen/immunogen. A “humoral immune response” refers to one that is at least in part mediated by antibodies. A “cellular immune response” is one mediated by T-lymphocytes or other white blood cells or both, and includes the production of cytokines, chemokines and similar molecules produced by activated T-cells, white blood cells, or both. Immune responses can be determined using standard immunoassays and neutralization assays, which are known in the art.

“Immunogenicity”, as used herein, refers to the capability of a protein or polypeptide to elicit an immune response directed specifically against a bacteria or virus that causes the identified disease.

Unless specifically indicated otherwise, the term “antibody,” as used herein, shall be understood to encompass antibody molecules comprising two immunoglobulin heavy chains and two immunoglobulin light chains (i.e., “full antibody molecules”) as well as antigen-binding fragments thereof. The terms “antigen-binding portion” of an antibody, “antigen-binding fragment” of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex.

Preparation of Human Antibodies

As disclosed herein, anti-RSV and or anti-RSV/anti-HMPF cross neutralizing antibodies by be obtained through B cell sorting techniques available to the artisan, and, for example, as described in the EXAMPLES below. Methods for generating human antibodies in transgenic mice are also known in the art and may be employed in order to derive antibodies in accordance with the present disclosure. Any such known methods can be used in the context of the present invention to make human antibodies that specifically bind to RSV-F (see, for example, U.S. Pat. No. 6,596,541).

In certain embodiments, the antibodies of the instant invention possess affinities (K_(D)) ranging from about 1.0×10−⁷M to about 1.0×10⁻¹²M, when measured by binding to antigen either immobilized on solid phase or in solution phase. In certain embodiments, the antibodies of the invention possess affinities (K_(D)) ranging from about 1×10⁻⁷ M to about 6×10⁻¹° M, when measured by binding to antigen either immobilized on solid phase or in solution phase. In certain embodiments, the antibodies of the invention possess affinities (K_(D)) ranging from about 1×10⁻⁷ M to about 9×10⁻¹⁰M, when measured by binding to antigen either immobilized on solid phase or in solution phase.

The anti-RSV-F and/or anti-HMPV antibodies and antibody fragments disclosed herein encompass proteins having amino acid sequences that vary from those of the described antibodies, but that retain the ability to bind RSV-F. Such variant antibodies and antibody fragments comprise one or more additions, deletions, or substitutions of amino acids when compared to parent sequence, but exhibit biological activity that is essentially equivalent to that of the described antibodies. Likewise, the antibody-encoding DNA sequences of the present invention encompass sequences that comprise one or more additions, deletions, or substitutions of nucleotides when compared to the disclosed sequence, but that encode an antibody or antibody fragment that is essentially bioequivalent to an antibody or antibody fragment of the invention.

Two antigen-binding proteins, or antibodies, are considered bioequivalent if, for example, they are pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose under similar experimental conditions, either single does or multiple dose. Some antibodies will be considered equivalents or pharmaceutical alternatives if they are equivalent in the extent of their absorption but not in their rate of absorption and yet may be considered bioequivalent because such differences in the rate of absorption are intentional and are reflected in the labeling, are not essential to the attainment of effective body drug concentrations on, e.g., chronic use, and are considered medically insignificant for the particular drug product studied.

In one embodiment, two antigen-binding proteins are bioequivalent if there are no clinically meaningful differences in their safety, purity, and potency.

In one embodiment, two antigen-binding proteins are bioequivalent if a patient can be switched one or more times between the reference product and the biological product without an expected increase in the risk of adverse effects, including a clinically significant change in immunogenicity, or diminished effectiveness, as compared to continued therapy without such switching.

In one embodiment, two antigen-binding proteins are bioequivalent if they both act by a common mechanism or mechanisms of action for the condition or conditions of use, to the extent that such mechanisms are known.

Bioequivalence may be demonstrated by in vivo and/or in vitro methods. Bioequivalence measures include, e.g., (a) an in vivo test in humans or other mammals, in which the concentration of the antibody or its metabolites is measured in blood, plasma, serum, or other biological fluid as a function of time; (b) an in vitro test that has been correlated with and is reasonably predictive of human in vivo bioavailability data; (c) an in vivo test in humans or other mammals in which the appropriate acute pharmacological effect of the antibody (or its target) is measured as a function of time; and (d) in a well-controlled clinical trial that establishes safety, efficacy, or bioavailability or bioequivalence of an antibody.

Bioequivalent variants of the antibodies of the invention may be constructed by, for example, making various substitutions of residues or sequences or deleting terminal or internal residues or sequences not needed for biological activity. For example, cysteine residues not essential for biological activity can be deleted or replaced with other amino acids to prevent formation of unnecessary or incorrect intramolecular disulfide bridges upon renaturation. In other contexts, bioequivalent antibodies may include antibody variants comprising amino acid changes, which modify the glycosylation characteristics of the antibodies, e.g., mutations that eliminate or remove glycosylation.

Biological and Biophysical Characteristics of the Antibodies

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof specifically bind to Respiratory Syncytial Virus (RSV) F protein (F), wherein at least one of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and/or CDRL3 amino acid sequences of such antibody or the antigen-binding fragment thereof is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99% identical; or 100% identical, and/or all percentages of identity in between; to at least one of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences as disclosed in Table 6 of an antibody selected from Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, such antibodies also possess at least one, two, three, four, five, six, seven, eight, nine, ten, or more characteristics disclosed in the immediately following eleven paragraphs.

Without wishing to be bound by any theory, it is believed that the inventive antibodies and antigen-binding fragments thereof may function by binding to RSV-F, preferably in the PreF conformation, and in so doing act to block the fusion of the viral membrane with the host cell membrane. The antibodies of the present invention may also function by binding to RSV-F and in so doing block the cell to cell spread of the virus and block syncytia formation associated with RSV infection of cells. Advantageously, both RSV subtype A and RSV subtype B are effectively blocked, or neutralized, by the majority of the anti-RSV antibodies disclosed herein.

In certain embodiments, the inventive antibodies and antigen-binding fragment thereof display better binding affinity for the PreF form of RSV-F relative to the PostF form of RSV-F.

In certain other embodiments, the inventive antibodies and antigen-binding fragments thereof advantageously display a clean or low polyreactivity profile (see, e.g., WO 2014/179363 and Xu et al., Protein Eng Des Sel, October; 26(10):663-70), and are thus particularly amenable to development as safe, efficacious, and developable therapeutic and/or prophylactic anti-RSV and/or HMPV treatments.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof, without wishing to be bound by any theory, may function by blocking or inhibiting RSV fusion to the cell membrane by binding to any one or more of, e.g., antigenic Sites Ø, I, II, III, IV, or Site V of the PreF conformation of the F protein. In certain embodiments, the inventive antibodies display antigenic site specificity for Site Ø, Site V, or Site III of PreF relative to RSV-F Site I, Site II, or Site IV.

In certain embodiments, at least a portion of the epitope with which the inventive antibodies and antigen-binding fragments thereof interacts comprises a portion of the α3 helix and β3/β4 hairpin of PreF. In certain embodiments, substantially all of the epitope of such antibodies comprises the α3 helix and β3/β4 hairpin of PreF. In still further embodiments, the inventive antibodies cross-compete with antibodies that recognize a portion or substantially all of the α3 helix and β3/β4 hairpin of PreF.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof display an in vitro neutralization potency (IC₅₀) of between about 0.5 microgram/milliliter (ug/ml) to about 5 ug/ml; between about 0.05 ug/ml to about 0.5 ug/ml; or less than about 0.05 mg/ml.

In certain embodiments, the binding affinity and/or epitopic specificity of the inventive antibodies and antigen-binding fragments thereof for any one of the RSV-F variants designated as 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG in FIG. 7A is reduced or eliminated relative to the binding affinity and/or epitopic specificity of said antibody or antigen-binding fragment thereof for the RSV-F or RSV-F DS-Cav1.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof display a cross-neutralization potency (IC₅₀) against human metapneumovirus (HMPV) as well as RSV. In certain such embodiments, the inventive antibodies and antigen-binding fragments thereof comprise at least one of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and/or CDRL3 amino acid sequences of such antibody or the antigen-binding fragment thereof is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99% identical; or 100% identical; and/or all percentages of identity in between; to at least one of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences as disclosed in Table 6 of Antibody Number 340 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with D25, MPE8, palivisumab, motavizumab, or AM-14. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with D25, MPE8, palivisumab, or motavizumab. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with MPE8, palivisumab, or motavizumab. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with D25, palivisumab, or motavizumab. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with D25. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with MPE8. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with palivisumab. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with motavizumab.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof complete with one or more of D25, MPE8, palivisumab, motavizumab, and/or AM-14.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof display at least about 2-fold; at least about 3-fold; at least about 4-fold; at least about 5-fold; at least about 6-fold; at least about 7-fold; at least about 8-fold; at least about 9-fold; at least about 10-fold; at least about 15-fold; at least about 20-fold; at least about 25-fold; at least about 30-fold; at least about 35-fold; at least about 40-fold; at least about 50-fold; at least about 55-fold; at least about 60-fold; at least about 70-fold; at least about 80-fold; at least about 90-fold; at least about 100-fold; greater than about 100-fold; and folds in between any of the foregoing; greater neutralization potency (IC50) than D25 and/or palivizumab.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRH3 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRH2 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRH1 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRL3 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRL2 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRL1 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise any combination of two, three, four, five, or six characteristics disclosed in the immediately preceeding six paragraphs.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise a heavy chain (HC) amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise a light chain (LC) amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise a heavy chain (HC) amino acid sequence and a light chain (LC) amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof are each selected from the group consisting antibodies that are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99% identical; or 100% identical; and/or all percentages of identity in between; to any one of the antibodies designated as Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise are each selected from the group consisting of the antibodies designated as Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.

In certain embodiments, isolated nucleic acid sequences are provided that encode antibodies or antigen binding fragments thereof that specifically bind to Respiratory Syncytial Virus (RSV) F protein and antigen-binding fragments thereof, wherein at least one of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and/or CDRL3 amino acid sequences of the antibody or the antigen-binding fragment thereof is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99% identical; or at least 100% identical and/or all percentages of identity in between; to at least one the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and/or CDRL3 amino acid sequences as disclosed in Table 6 of an antibody selected from Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRH3 amino acid sequence of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRH2 amino acid sequences of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRH1 amino acid sequences of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRL3 amino acid sequences of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRL2 amino acid sequences of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRL1 amino acid sequences of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the heavy chain (HC) amino acid sequences of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the heavy chain (LC) amino acid sequences of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences are each selected from the group consisting of sequences that are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99% identical; at least 100% identical, and/or all percentages of identity in between; to any one of the nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, expression vectors are provided comprising the isolated nucleic acid sequences disclose herein and throughout, and in particular in the immediately preceding ten paragraphs.

In certain embodiments, host cells transfected, transformed, or transduced with the nucleic acid sequences and/or the expression vectors disclosed immediately above are provided.

Epitope Mapping and Related Technologies

As described above and as demonstrated in the EXAMPLES, Applicant has characterized the epitopic specificities, bin assignments, and antigenic site assignments of the inventive antibodies and antigen-binding fragments thereof. In addition to the methods for conducting such characterization, various other techniques are available to the artisan that can be used to carry out such characterization or to otherwise ascertain whether an antibody “interacts with one or more amino acids” within a polypeptide or protein. Exemplary techniques include, for example, a routine cross-blocking assay such as that described Antibodies, Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harb., N.Y.) can be performed. Other methods include alanine scanning mutational analysis, peptide blot analysis (Reineke (2004) Methods Mol Biol 248:443-63), peptide cleavage analysis crystallographic studies and NMR analysis. In addition, methods such as epitope excision, epitope extraction and chemical modification of antigens can be employed (Tomer (2000) Protein Science 9: 487-496). Another method that can be used to identify the amino acids within a polypeptide with which an antibody interacts is hydrogen/deuterium exchange detected by mass spectrometry. In general terms, the hydrogen/deuterium exchange method involves deuterium-labeling the protein of interest, followed by binding the antibody to the deuterium-labeled protein. Next, the protein/antibody complex is transferred to water and exchangeable protons within amino acids that are protected by the antibody complex undergo deuterium-to-hydrogen back-exchange at a slower rate than exchangeable protons within amino acids that are not part of the interface. As a result, amino acids that form part of the protein/antibody interface may retain deuterium and therefore exhibit relatively higher mass compared to amino acids not included in the interface. After dissociation of the antibody, the target protein is subjected to protease cleavage and mass spectrometry analysis, thereby revealing the deuterium-labeled residues that correspond to the specific amino acids with which the antibody interacts. See, e.g., Ehring (1999) Analytical Biochemistry 267 (2):252-259; Engen and Smith (2001) Anal. Chem. 73:256A-265A.

As the artisan will understand, an epitope can be formed both from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, and more usually, at least 5 or 8-10 amino acids in a unique spatial conformation.

Modification-Assisted Profiling (MAP), also known as Antigen Structure-based Antibody Profiling (ASAP) is a method that categorizes large numbers of monoclonal antibodies (mAbs) directed against the same antigen according to the similarities of the binding profile of each antibody to chemically or enzymatically modified antigen surfaces (U.S. Publ. No. 2004/0101920). Each category may reflect a unique epitope either distinctly different from or partially overlapping with epitope represented by another category. This technology allows rapid filtering of genetically identical antibodies, such that characterization can be focused on genetically distinct antibodies. When applied to hybridoma screening, MAP may facilitate identification of rare hybridoma clones that produce mAbs having the desired characteristics. MAP may be used to sort the antibodies of the invention into groups of antibodies binding different epitopes.

In certain embodiments, the inventive antibodies and/or antigen-binding fragments thereof interact with an amino acid sequence comprising the amino acid residues that are altered in one or more of the F protein patch variants disclosed, e.g., in the EXAMPLES and which are depicted in, e.g., FIG. 7A and which are designated as RSV F Variants 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG. In certain embodiments, such inventive antibodies and antigen-binding fragments thereof interact with an amino acid sequence comprising the amino acid residues that are altered in RSV F Variant 2. In certain embodiments, the inventive antibodies and/or antigen-binding fragments thereof interact with amino acid residues that extend beyond the region(s) identified above by about 5 to 10 amino acid residues, or by about 10 to 15 amino acid residues, or by about 15 to 20 amino acid residues towards either the amino terminal or the carboxy terminal of the RSV-F protein.

In certain embodiments, the antibodies of the present invention do not bind to the same epitope on RSV-F protein as palivizumab, motavizumab, MPE8, or AM-14.

As the artisan understands, one can easily determine whether an antibody binds to the same epitope as, or competes for binding with, a reference anti-RSV-F antibody by using routine methods available in the art. For example, to determine if a test antibody binds to the same epitope as a reference RSV-F antibody of the invention, the reference antibody is allowed to bind to a RSV-F protein or peptide under saturating conditions. Next, the ability of a test antibody to bind to the RSV-F molecule is assessed. If the test antibody is able to bind to RSV-F following saturation binding with the reference anti-RSV-F antibody, it can be concluded that the test antibody binds to a different epitope than the reference anti-RSV-F antibody. On the other hand, if the test antibody is not able to bind to the RSV-F molecule following saturation binding with the reference anti-RSV-F antibody, then the test antibody may bind to the same epitope as the epitope bound by the reference anti-RSV-F antibody of the invention.

To determine if an antibody competes for binding with a reference anti-RSV-F antibody, the above-described binding methodology is performed in two orientations: In a first orientation, the reference antibody is allowed to bind to a RSV-F molecule under saturating conditions followed by assessment of binding of the test antibody to the RSV-F molecule. In a second orientation, the test antibody is allowed to bind to a RSV-F molecule under saturating conditions followed by assessment of binding of the reference antibody to the RSV-F molecule. If, in both orientations, only the first (saturating) antibody is capable of binding to the RSV-F molecule, then it is concluded that the test antibody and the reference antibody compete for binding to RSV-F. As will be appreciated by a person of ordinary skill in the art, an antibody that competes for binding with a reference antibody may not necessarily bind to the identical epitope as the reference antibody, but may sterically block binding of the reference antibody by binding an overlapping or adjacent epitope.

Two antibodies bind to the same or overlapping epitope if each competitively inhibits (blocks) binding of the other to the antigen. That is, a 1-, 5-, 10-, 20- or 100-fold excess of one antibody inhibits binding of the other by at least 50% but preferably 75%, 90% or even 99% as measured in a competitive binding assay (see, e.g., Junghans et al., Cancer Res. (1990) 50:1495-1502). Alternatively, two antibodies have the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other. Two antibodies have overlapping epitopes if some amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other.

Additional routine experimentation (e.g., peptide mutation and binding analyses) can then be carried out to confirm whether the observed lack of binding of the test antibody is in fact due to binding to the same epitope as the reference antibody or if steric blocking (or another phenomenon) is responsible for the lack of observed binding. Experiments of this sort can be performed using ELISA, RIA, surface plasmon resonance, flow cytometry or any other quantitative or qualitative antibody-binding assay available in the art.

Immunoconjugates

The invention encompasses a human RSV-F monoclonal antibody conjugated to a therapeutic moiety (“immunoconjugate”), such as an agent that is capable of reducing the severity of primary infection with RSV and/or HMPV, or to ameliorate at least one symptom associated with RSV infection and/or HMPV infection, including coughing, fever, pneumonia, or the severity thereof. Such an agent may be a second different antibody to RSV-F and/or HMPV, or a vaccine. The type of therapeutic moiety that may be conjugated to the anti-RSV-F antibody and/or anti-HMPV antibody and will take into account the condition to be treated and the desired therapeutic effect to be achieved. Alternatively, if the desired therapeutic effect is to treat the sequelae or symptoms associated with RSV and/or HMPV infection, or any other condition resulting from such infection, such as, but not limited to, pneumonia, it may be advantageous to conjugate an agent appropriate to treat the sequelae or symptoms of the condition, or to alleviate any side effects of the antibodies of the invention. Examples of suitable agents for forming immunoconjugates are known in the art, see for example, WO 05/103081.

Multi-Specific Antibodies

The antibodies of the present invention may be mono-specific, bi-specific, or multi-specific. Multi-specific antibodies may be specific for different epitopes of one target polypeptide or may contain antigen-binding domains specific for more than one target polypeptide. See, e.g., Tutt et al., 1991, J. Immunol. 147:60-69; Kufer et al., 2004, Trends Biotechnol. 22:238-244. The antibodies of the present invention can be linked to or co-expressed with another functional molecule, e.g., another peptide or protein. For example, an antibody or fragment thereof can be functionally linked {e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody or antibody fragment to produce a bi-specific or a multi-specific antibody with a second binding specificity.

An exemplary bi-specific antibody format that can be used in the context of the present invention involves the use of a first immunoglobulin (Ig) C_(H)3 domain and a second Ig C_(H)3 domain, wherein the first and second Ig C_(H)3 domains differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces binding of the bi-specific antibody to Protein A as compared to a bi-specific antibody lacking the amino acid difference. In one embodiment, the first Ig C_(H)3 domain binds Protein A and the second Ig C_(H)3 domain contains a mutation that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering; H435R by EU numbering). The second C_(H)3 may further comprise a Y96F modification (by IMGT; Y436F by EU). Further modifications that may be found within the second C_(H3) include: D16E, L18M, N44S, K52N, V57M, and V82I (by IMGT; D356E, L358M, N384S, K392N, V397M, and V422I by EU) in the case of IgG1 antibodies; N44S, K52N, and V82I (IMGT; N384S, K392N, and V422I by EU) in the case of IgG2 antibodies; and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I by EU) in the case of IgG4 antibodies. Variations on the bi-specific antibody format described above are contemplated within the scope of the present invention.

Therapeutic Administration and Formulations

The invention provides therapeutic compositions (including pharmaceutical compositions) comprising the inventive anti-RSV-F and/or HMPV antibodies or antigen-binding fragments thereof. The administration of therapeutic compositions in accordance with the invention will be administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. “Compendium of excipients for parenteral formulations” PDA (1998) J Pharm Sci Technol 52:238-31 1.

The dose of each of the antibodies of the invention may vary depending upon the age and the size of a subject to be administered, target disease, conditions, route of administration, and the like. When the antibodies of the present invention are used for treating a RSV infection and/or HMPV infection in a patient, or for treating one or more symptoms associated with a RSV infection and/or HMPV infection, such as the cough or pneumonia associated with a RSV infection and/or HMPV in a patient, or for lessening the severity of the disease, it is advantageous to administer each of the antibodies of the present invention intravenously or subcutaneously normally at a single dose of about 0.01 to about 30 mg/kg body weight, more preferably about 0.1 to about 20 mg/kg body weight, or about 0.1 to about 15 mg/kg body weight, or about 0.02 to about 7 mg/kg body weight, about 0.03 to about 5 mg/kg body weight, or about 0.05 to about 3 mg/kg body weight, or about 1 mg/kg body weight, or about 3.0 mg/kg body weight, or about 10 mg/kg body weight, or about 20 mg/kg body weight. Multiple doses may be administered as necessary. Depending on the severity of the condition, the frequency and the duration of the treatment can be adjusted. In certain embodiments, the antibodies or antigen-binding fragments thereof of the invention can be administered as an initial dose of at least about 0.1 mg to about 800 mg, about 1 mg to about 600 mg, about 5 mg to about 300 mg, or about 10 mg to about 150 mg, to about 100 mg, or to about 50 mg. In certain embodiments, the initial dose may be followed by administration of a second or a plurality of subsequent doses of the antibodies or antigen-binding fragments thereof in an amount that can be approximately the same or less than that of the initial dose, wherein the subsequent doses are separated by at least 1 day to 3 days; at least one week, at least 2 weeks; at least 3 weeks; at least 4 weeks; at least 5 weeks; at least 6 weeks; at least 7 weeks; at least 8 weeks; at least 9 weeks; at least 10 weeks; at least 12 weeks; or at least 14 weeks.

Various delivery systems are known and can be used to administer the pharmaceutical composition of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor mediated endocytosis (see, e.g., Wu et al. (1987) J. Biol. Chem. 262:4429-4432). Methods of introduction include, but are not limited to, intradermal, transdermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural and oral routes. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings {e.g., oral mucosa, nasal mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. It may be delivered as an aerosolized formulation (See U.S. Publ. No. 2011/0311515 and U.S. Publ. No. 2012/0128669). The delivery of agents useful for treating respiratory diseases by inhalation is becoming more widely accepted (See A. J. Bitonti and J. A. Dumont, (2006), Adv. Drug Deliv. Rev, 58:1 106-1118). In addition to being effective at treating local pulmonary disease, such a delivery mechanism may also be useful for systemic delivery of antibodies (See Maillet et al. (2008), Pharmaceutical Research, Vol. 25, No. 6, 2008).

The pharmaceutical composition can be also delivered in a vesicle, in particular a liposome (see, for example, Langer (1990) Science 249:1527-1533).

In certain situations, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump may be used. In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in proximity of the composition's target, thus requiring only a fraction of the systemic dose.

The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by methods publicly known. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared is preferably filled in an appropriate ampoule.

A pharmaceutical composition of the present invention can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, with respect to subcutaneous delivery, a pen delivery device readily has applications in delivering a pharmaceutical composition of the present invention. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

Numerous reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of a pharmaceutical composition of the present invention. Examples include, but certainly are not limited to AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Burghdorf, Switzerland), HUMALOG MIX 75/25™ pen, HUMALOG™ pen, HUMALIN 70/30™ pen (Eli Lilly and Co., Indianapolis, Ind.), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, N.J.), OPTIPEN™, OPTIPEN PRO™ OPTIPEN STARLET™, and OPTICLIK™ (Sanofi-Aventis, Frankfurt, Germany), to name only a few. Examples of disposable pen delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the present invention include, but certainly are not limited to the SOLOSTAR™ pen (Sanofi-Aventis), the FLEXPEN™ (Novo Nordisk), and the KWIKPEN™ (Eli Lilly), the SURECLICK™ Autoinjector (Amgen, Thousand Oaks, Calif.), the PENLET™ (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, L.P.) and the HUMIRA™ Pen (Abbott Labs, Abbott Park, Ill.), to name only a few.

Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc. The amount of the aforesaid antibody contained is generally about 5 to about 500 mg per dosage form in a unit dose; especially in the form of injection, it is preferred that the aforesaid antibody is contained in about 5 to about 100 mg and in about 10 to about 250 mg for the other dosage forms.

Administration Regimens

According to certain embodiments, multiple doses of an antibody to RSV-F and/or HMPV, or a pharmaceutical composition comprising or encoding for these antibodies, may be administered to a subject over a defined time course. The methods according to this aspect of the invention comprise sequentially administering to a subject multiple doses of an antibody to RSV-F and/or HMPV, or sequentially administering to a subject multiple doses of a pharmaceutical composition comprising or encoding for an antibody of the invention or antigen binding fragment therof. As used herein, “sequentially administering” means that each dose of antibody to RSV-F and/or HMPV, or the pharmaceutical composition, is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months). The present invention includes methods which comprise sequentially administering to the patient a single initial dose of an antibody to RSV-F and/or HMPV, or a composition comprising or encoding for the antibodies, followed by one or more secondary doses of the antibody to RSV-F and/or HMPV, or the composition, and optionally followed by one or more tertiary doses of the antibody to RSV-F and/or HMPV, or the composition.

The terms “initial dose,” “secondary doses,” and “tertiary doses,” refer to the temporal sequence of administration of the antibody to RSV-F and/or HMPV or the compositions of the invention. Thus, the “initial dose” is the dose which is administered at the beginning of the treatment regimen (also referred to as the “baseline dose”); the “secondary doses” are the doses which are administered after the initial dose; and the “tertiary doses” are the doses which are administered after the secondary doses. The initial, secondary, and tertiary doses may all contain the same amount of antibody to RSV-F and/or HMPV, but generally may differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of antibody to RSV-F and/or HMPV contained in the initial, secondary and/or tertiary doses vary from one another (e.g., adjusted up or down as appropriate) during the course of treatment. In certain embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as “loading doses” followed by subsequent doses that are administered on a less frequent basis (e.g., “maintenance doses”).

In one exemplary embodiment of the present invention, each secondary and/or tertiary dose is administered 1 to 26 (e.g., 1 , ½, 2, 2½, 3, 3½, 4, 4½, 5, 5½, 6, 6½, 7 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12, 12½, 13, 13½, 14, 14½, 15, 15½, 16, 16½, 17, 17½, 18, 18½, 19, 19½, 20, 20½, 21, 21½, 22, 22½, 23, 23½, 24, 24½, 25, 25½, 26, 26½, or more) weeks after the immediately preceding dose. The phrase “the immediately preceding dose,” as used herein, means, in a sequence of multiple administrations, the dose of antibody to RSV-F and/or HMPV which is administered to a patient prior to the administration of the very next dose in the sequence with no intervening doses.

The methods according to this aspect of the invention may comprise administering to a patient any number of secondary and/or tertiary doses of an antibody to RSV-F and/or HMPV. For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Likewise, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.

In embodiments involving multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 2 weeks after the immediately preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2 to 4 weeks after the immediately preceding dose. Alternatively, the frequency at which the secondary and/or tertiary doses are administered to a patient can vary over the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by a physician depending on the needs of the individual patient following clinical examination.

Accordingly, in certain embodiments are provided pharmaceutical compositions comprising: one or more of the inventive antibodies or antigen-binding fragments thereof disclosed herein and throughout and a pharmaceutically acceptable carrier and/or one or more excipients. In certain other embodiments are provided pharmaceutical compositions comprising: one or more nucleic acid sequences encoding one or more inventive antibodies or antigen-binding fragments thereof; or one or more the expression vectors harbouring such nucleic acid sequences; and a pharmaceutically acceptable carrier and/or one or more excipients.

Therapeutic Uses of the Antibodies and Pharmaceutical Compositions

Due to their binding to and interaction with the RSV fusion protein (RSV-F), it is believed that the inventive antibodies and antigen-binding fragments thereof are useful—without wishing to be bound to any theory—for preventing fusion of the virus with the host cell membrane, for preventing cell to cell virus spread, and for inhibition of syncytia formation. Additionally, as Applicant has demonstrated herein that, surprisingly, a subset of the inventive anti-RSV antibodies and antigen-binding fragment thereof display crass-neutralizing potency agains HMPV, the inventive antibodies and antigen-binding fragments thereof are advantageous for preventing an infection of a subject with RSV and/or HMPV when administered prophylactically. Alternatively, the antibodies of the present invention may be useful for ameliorating at least one symptom associated with the infection, such as coughing, fever, pneumonia, or for lessening the severity, duration, and/or frequency of the infection. The antibodies of the invention are also contemplated for prophylactic use in patients at risk for developing or acquiring an RSV infection and/or HMPV infection. These patients include pre-term infants, full term infants born during RSV season (late fall to early spring), the elderly (for example, in anyone 65 years of age or older) and/or HMPV season, or patients immunocompromised due to illness or treatment with immunosuppressive therapeutics, or patients who may have an underlying medical condition that predisposes them to an RSV infection (for example, cystic fibrosis patients, patients with congestive heart failure or other cardiac conditions, patients with airway impairment, patients with COPD) and/or HMPV infection. It is contemplated that the antibodies of the invention may be used alone, or in conjunction with a second agent, or third agent for treating RSV infection and/or HMPV infection, or for alleviating at least one symptom or complication associated with the RSV infection and/or HMPV infection, such as the fever, coughing, bronchiolitis, or pneumonia associated with, or resulting from such an infection. The second or third agents may be delivered concurrently with the antibodies of the invention, or they may be administered separately, either before or after the antibodies of the invention. The second or third agent may be an anti-viral such as ribavirin, an NSAID or other agents to reduce fever or pain, another second but different antibody that specifically binds RSV-F, an agent (e.g. an antibody) that binds to another RSV antigen, such as RSV-G, a vaccine against RSV, an siRNA specific for an RSV antigen.

In yet a further embodiment of the invention the present antibodies are used for the preparation of a pharmaceutical composition for treating patients suffering from a RSV infection and/or HMPV infection. In yet another embodiment of the invention the present antibodies are used for the preparation of a pharmaceutical composition for reducing the severity of a primary infection with RSV and/or HMPV, or for reducing the duration of the infection, or for reducing at least one symptom associated with the RSV infection and/or the HMPV infection. In a further embodiment of the invention the present antibodies are used as adjunct therapy with any other agent useful for treating an RSV infection and/or and HMPV infectin, including an antiviral, a toxoid, a vaccine, a second RSV-F antibody, or any other antibody specific for an RSV antigen, including an RSV-G antibody, or any other palliative therapy known to those skilled in the art.

Accordingly, in certain embodiments are provided methods of treating or preventing a Respiratory Syncytial Virus (RSV) infection, or at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof one or more of the inventive antibodies or antigen-binding fragments thereof disclosed herein and throughout (or pharmaceutical composition of the invention), such as, e.g., one or more of the anti-RSV antibodies disclosed in Table 6, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.

In certain other embodiments are provided methods of treating or preventing a Respiratory Syncytial Virus (RSV) infection, or at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a nucleic acid sequence encoding one or more of the inventive antibodies or antigen-binding fragments thereof, such nucleic acid sequenced disclosed in Table 6 and compliments thereof, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.

In additional embodiments are provided methods of treating or preventing a Respiratory Syncytial Virus (RSV) infection, are at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a host cell harboring a nucleic acid sequence or an expression vector comprising such a nucleic aci sequence, wherein such nucleic acid sequences is selected from the group consisting of sequences disclosed in Table 6 and compliments thereof, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.

In additional embodiments are provided methods of treating or preventing a Respiratory Syncytial Virus (RSV) infection, are at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a pharmaceutical composition comprising either: one or more of the inventive antibodies or antigen-binding fragments thereof as disclosed in Table 6; one or more nucleic acid sequences or an expression vectors comprising such a nucleic acid sequence, wherein such nucleic acid sequences are selected from the group consisting of sequences disclosed in Table 6 and compliments thereof; one or more host cells harboring one or more nucleic acid sequences or an expression vectors comprising such one or more nucleic acid sequences, wherein such nucleic acid sequences are selected from the group consisting of sequences disclosed in Table 6 and compliments thereof; and a pharmaceutically acceptable carrier and/or one or more excipients, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.

In certain embodiments are provided methods of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, are at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof one or more of the inventive antibodies or antigen-binding fragments thereof disclosed herein and throughout, such as, e.g., one or more of the anti-RSV antibodies disclosed in Table 6, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity. In certain embodiments, the one or more antibodies or antigen-binding fragments thereof comprises Antibody Number 340 as disclosed in Table 6.

In certain other embodiments are provided methods of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, are at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a nucleic acid sequence encoding one or more of the inventive antibodies or antigen-binding fragments thereof, such nucleic acid sequenced disclosed in Table 6 and compliments thereof, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity. In certain embodiments, the one or more antibodies or antigen-binding fragments thereof comprises Antibody Number 340 as disclosed in Table 6.

In additional embodiments are provided methods of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, are at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a host cell harboring a nucleic acid sequence or an expression vector comprising such a nucleic acid sequence, wherein such nucleic acid sequences is selected from the group consisting of sequences disclosed in Table 6 and compliments thereof, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity. In certain embodiments, the one or more antibodies or antigen-binding fragments thereof comprises Antibody Number 340 as disclosed in Table 6.

In additional embodiments are provided methods of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, are at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a pharmaceutical composition comprising either: one or more of the inventive antibodies or antigen-binding fragments thereof as disclosed in Table 6; one or more nucleic acid sequences or an expression vectors comprising such a nucleic acid sequence, wherein such nucleic acid sequences are selected from the group consisting of sequences disclosed in Table 6 and compliments thereof; one or more host cells harboring one or more nucleic acid sequences or an expression vectors comprising suchone or more nucleic acid sequences, wherein such nucleic acid sequences are selected from the group consisting of sequences disclosed in Table 6 and compliments thereof; and a pharmaceutically acceptable carrier and/or one or more excipients, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity. In certain embodiments, the one or more antibodies or antigen-binding fragments thereof comprises Antibody Number 340 as disclosed in Table 6.

Combination Therapies

As noted above, according to certain embodiments, the disclosed methods comprise administering to the subject one or more additional therapeutic agents in combination with an antibody to RSV-F and or HMPV. As used herein, the expression “in combination with” means that the additional therapeutic agents are administered before, after, or concurrent with the pharmaceutical composition comprising the anti-RSV-F antibody. The term “in combination with” also includes sequential or concomitant administration of the anti-RSV-F antibody and a second therapeutic agent.

For example, when administered “before” the pharmaceutical composition comprising the anti-RSV-F antibody, the additional therapeutic agent may be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes or about 10 minutes prior to the administration of the pharmaceutical composition comprising the anti-RSV-F antibody. When administered “after” the pharmaceutical composition comprising the anti-RSV-F antibody, the additional therapeutic agent may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours or about 72 hours after the administration of the pharmaceutical composition comprising the anti-RSV-F antibodies. Administration “concurrent” or with the pharmaceutical composition comprising the anti-RSV-F antibody means that the additional therapeutic agent is administered to the subject in a separate dosage form within less than 5 minutes (before, after, or at the same time) of administration of the pharmaceutical composition comprising the anti-RSV-F antibody, or administered to the subject as a single combined dosage formulation comprising both the additional therapeutic agent and the anti-RSV-F antibody.

Combination therapies may include an anti-RSV-F antibody of the invention and any additional therapeutic agent that may be advantageously combined with an antibody of the invention, or with a biologically active fragment of an antibody of the invention.

For example, a second or third therapeutic agent may be employed to aid in reducing the viral load in the lungs, such as an antiviral, for example, ribavirin. The antibodies may also be used in conjunction with other therapies, as noted above, including a toxoid, a vaccine specific for RSV, a second antibody specific for RSV-F, or an antibody specific for another RSV antigen, such as RSV-G.

Diagnostic Uses of the Antibodies

The inventive anti-RSV antibodies and antigen-binding fragments thereof may also be used to detect and/or measure RSV and/or HMPV in a sample, e.g., for diagnostic purposes. It is envisioned that confirmation of an infection thought to be caused by RSV and/or HMPV may be made by measuring the presence of the virus through use of any one or more of the antibodies of the invention. Exemplary diagnostic assays for RSV and/or HMPV may comprise, e.g., contacting a sample, obtained from a patient, with an anti-RSV-F and/or HMPV antibody of the invention, wherein the anti-RSV-F and/or HMPV antibody is labeled with a detectable label or reporter molecule or used as a capture ligand to selectively isolate the virus containing the F protein from patient samples. Alternatively, an unlabeled anti-RSV-F and/or HMPV antibody can be used in diagnostic applications in combination with a secondary antibody which is itself detectably labeled. The detectable label or reporter molecule can be a radioisotope, such as ³H, ¹⁴C, ³²P, ³⁵S, or ¹²⁵l; a fluorescent or chemiluminescent moiety such as fluorescein isothiocyanate, or rhodamine; or an enzyme such as alkaline phosphatase, β-galactosidase, horseradish peroxidase, or luciferase. Specific exemplary assays that can be used to detect or measure RSV containing the F protein and/or HMPV in a sample include enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), and fluorescence-activated cell sorting (FACS).

Samples that can be used in RSV and/or HMPV diagnostic assays according to the present invention include any tissue or fluid sample obtainable from a patient, which contains detectable quantities of RSV-F protein and/or HMPV, or fragments thereof, under normal or pathological conditions. Generally, levels of RSV-F and/or HMPV in a particular sample obtained from a healthy patient (e.g., a patient not afflicted with a disease or condition associated with the presence of RSV-F and/or HMPV) will be measured to initially establish a baseline, or standard, level of the F protein from RSV and/or HMPV. This baseline level of RSV-F and/or HMPV can then be compared against the levels of RSV-F and/or HMPV measured in samples obtained from individuals suspected of having an RSV and/or HMPV infection, or symptoms associated with such infection.

EXAMPLES

Applicant has comprehensively profiled the human antibody response to RSV fusion protein (F) by isolating and characterizing 133 RSV F-specific monoclonal antibodies from the memory B cells of a healthy adult donor, and used these antibodies to comprehensively map the antigenic topology of RSV F. The antibody response to RSV F was determined to be comprised of a broad diversity of clones that target several antigenic sites. Nearly half of the most potent antibodies target a previously undefined site of vulnerability near the apex of the prefusion conformation of RSV F (preF), providing strong support for the development of RSV antibodies that target this region, as well as vaccine candidates that preserve the membrane-distal hemisphere of the preF protein. Additionally, this class of antibodies displayed convergent sequence features, thus providing a future means to rapidly detect these types of antibodies in human samples. Many of the antibodies that bound preF-specific surfaces from this donor were over 100 times more potent than palivizumab, and one antibody cross-neutralized human metapneumovirus (HMPV). Taken together, the results have implications for the design and evaluation of RSV vaccine and antibody-based therapeutic candidates, and offer new options for passive prophylaxis.

Large-Scale Isolation of RSV F-Specific Monoclonal Antibodies from Healthy Adult Human Donors

In order to comprehensively profile the human antibody response to RSV F, Applicant isolated and characterized 133 monoclonal antibodies from the memory B cells of a healthy adult donor (“donor 006”). Although this donor did not have a documented history of RSV infection, healthy adults are expected to have had multiple RSV infections throughout life (26).

The magnitude of the memory B cell response in this donor to RSV F was assessed by staining peripheral B cells with a mixture of fluorescently labeled pre- and postfusion RSV F sorting probes (FIG. 6A through 6B) (11, 15). Both proteins were dual-labeled in order to eliminate background due to non-specific fluorochrome binding (27). Flow cytometric analysis revealed that 0.04-0.18% of class-switched (IgG⁺ and IgA⁺) peripheral B cells were specific for RSV F (FIG. 1A and FIG. B), which is significantly lower than the percentage of RSV F-specific cells observed after experimental RSV infection and suggests that this donor was probably not recently exposed to RSV (28). Notably, index sorting showed that 17-38% of circulating RSV F-specific B cells express IgA, indicating that IgA memory B cells to RSV F are present in peripheral blood (FIG. 1B).

Approximately 200 RSV F-specific B cells were single-cell sorted from the donor sample, and antibody variable heavy (VH) and variable light (VL) chain genes were rescued by single-cell PCR (29). One hundred thirty-three (133) cognate heavy and light chain pairs were subsequently cloned and expressed as full-length IgGs in an engineered strain of Saccharomyces cerevisiae for further characterization (30). Preliminary binding studies showed that approximately 80% of antibodies cloned from RSV F glycoprotein (F)-specific B cells bound to recombinant RSV F proteins.

Sequence Analysis of RSV F-Specific Antibody Repertoires

Sequence analysis of the isolated monoclonal antibodies revealed that the RSV-F specific repertoire was highly diverse, containing over 70 unique lineages (FIG. 1C and Table 2). This result is in stark contrast to the relatively restricted repertoires observed in HIV-infected patients (31), or in healthy donors after influenza vaccination (32). Compared to non-RSV-reactive antibodies (33), the RSV F-specific repertoires were skewed, generally, toward certain VH germline genes (VH1-18, VH1-2, VH1-69, VH2-70, VH4-304, and VH5-51) (FIG. 1D and Table 2) and longer heavy chain third complementarity-determining region (CDRH3) lengths (generally, approximately 14-18 amino acids in length; FIG. 1E and Table 2). Interestingly, a bias toward VH1-69 has also been observed in anti-HIV-1, anti-influenza, and anti-HCV repertoires (34-36), and recent studies have shown that there is a significant increase in the relative usage of VH1-18, VH1-2, and VH1-69 during acute dengue infection (37). Hence, it appears that these particular germline gene segments may have inherent properties that facilitate recognition of viral envelope proteins.

The average level of somatic hypermutation (SHM) ranged generally between 16 and 30 nucleotide substitutions per VH gene (excluding CDRH3) (FIG. 1F and Table 2), which is comparable to the average level of SHM observed in anti-influenza antibody repertoires (32, 38) and consistent with the recurrent nature of RSV infection (26). Interestingly, several antibodies contained 40 or greater VH gene nucleotide substitutions, suggesting that multiple rounds of RSV infection can result in antibodies with very high levels of somatic hypermutation (SHM).

A Large Proportion of Antibodies Bind Exclusively to PreF

We next measured the apparent binding affinities of the IgGs to furin-cleaved RSV F ectodomains stabilized in the prefusion (DS-Cav1) or postfusion (F ΔFP) conformation using biolayer interferometry (11, 15). A relatively large proportion of the antibodies (36-67%) bound exclusively to preF (FIG. 2A and FIG. B; Table 3). The vast majority of remaining antibodies bound to both pre- and postF, with only 5-7% of antibodies showing exclusive postF specificity (FIG. 2A and FIG. B; Table 3). The low prevalence of postF-specific antibodies in these donor repertoires is consistent with the observation that less than 10% of anti-RSV F serum-binding activity specifically targets postF (8). Interestingly, however, the majority of cross-reactive antibodies bound with higher apparent affinity to postF (FIG. 2A; Table 3), suggesting that these antibodies were probably elicited by and/or affinity matured against postF in vivo. Hence, the significantly higher proportion of preF- versus postF-specific antibodies is likely due to the higher immunogenicity of the unique surfaces on preF compared to postF, rather than an increased abundance of preF in vivo. Finally, as expected based on the relatively high degree of sequence conservation between RSV subtypes, most of the antibodies showed binding reactivity to F proteins derived from both subtypes A and B (FIG. 2C; Table 3).

Since certain antiviral antibody specificities have been associated with poly- and autoreactivity (39-41), we also tested the RSV antibodies for polyreactivity using a previously described high-throughput assay that correlates with down-stream behaviors such as serum clearance (42, 43). One hundred and seventy-seven clinical antibodies, as well as several broadly neutralizing HIV antibodies, were also included for comparison. Interestingly, in contrast to many previously described HIV broadly neutralizing antibodies, the vast majority of RSV F-specific antibodies lacked significant polyreactivity in this assay (FIG. 2D).

RSV F-Specific Antibodies Target Six Major Antigenic Sites

To map the antigenic specificities of the RSV F-specific antibodies, Applicant first performed competitive binding experiments using a previously described yeast-based assay (44). Antibodies were initially tested for competition with D25, AM14 and MPE8—three previously described preF-specific antibodies (10, 17, 21)—and motavizumab, an affinity-matured variant of palivizumab that binds to both pre- and postF (10, 11, 45). Non-competing antibodies were then tested for competition with a site IV-directed mAb (101F) (46), a site I-directed antibody (Site I Ab), and two high affinity antibodies (High Affinity Ab I and High Affinity Ab 2, respectively) that did not strongly compete with each other or any of the control antibodies. Each antibody was assigned a bin based on the results of this competition assay (see, e.g., Table 4).

In order to confirm and increase the resolution of our epitope assignments, the binding of each antibody to a panel of preF variants was measured using a luminex-based assay. Each variant contained 2-4 mutations clustered together to form a patch on the surface of preF. A total of nine patches that uniformly covered the surface of preF were generated (FIG. 7A through FIG. 7C). Deglycosylated preF was also included to identify antibodies targeting glycan-dependent epitopes. Binding of each antibody to the 10 preF variants was compared to that of wild-type preF and used to assign a patch (see, e.g., Table 4). Previously characterized antibodies D25, AM14 and motavizumab were used to validate the assay (se, e.g., FIG. 7C and Table 4). The combined bin and patch data were then used to assign each antibody to a single antigenic site (FIG. 3A through FIG. 3G), which were defined based on previously determined structures, resistance mutations, and secondary structure elements of the F protein. Overall, these data show that the large majority of isolated antibodies target six dominant antigenic sites on prefusion RSV F (Ø, I, II, III, IV, and V). Interestingly, only a small proportion of the isolated antibodies had binding profiles similar to that of AM14, suggesting that antibodies targeting this quaternary epitope are not commonly elicited during natural infection. None of the antibodies were sensitive to deglycosylation of F, demonstrating that glycan-dependent antibodies are also rarely elicited by natural RSV infection.

Analysis of the preF- and postF-binding activities of the antibodies targeting each antigenic site (see, e.g., FIG. 3C through FIG. 3G; Table 4) revealed that three sites are primarily found on preF (Ø, III, and V). Antibodies targeting site 0 and site III have been previously described (10, 17), and these sites are located on the top and side of the preF spike, respectively. Approximately 18% of the antibodies from this donor recognized site 0 and approximately 20% recognized site III. A relatively large proportion of antibodies from this donor (approximately 26%) recognized the third preF-specific site, which has not been previously described and therefore has been designated herein as region site V (See, e.g., FIG. 3C through FIG. 3G; Table 4). The majority of site V antibodies competed with D25, MPE8 and motavizumab, which was unexpected given the distance between the epitopes recognized by these three antibodies. The patch mutant analysis revealed that these antibodies interact with the α3 helix and β3/β4 hairpin of preF. This region is located between the epitopes recognized by D25, MPE8, and motavizumab, explaining the unusual competition profile observed for this class of antibodies (See, e.g., FIG. 8). In addition to the three primarily preF-specific sites, a large number of the antibodies that recognized antigenic site IV were preF-specific, likely due to contacts with β22, which dramatically rearranges during the transition from pre- to postF. In summary, the epitope mapping data show that the large majority of isolated antibodies target six dominant antigenic sites, approximately half of which are exclusively expressed on preF.

Highly Potent Neutralizing Antibodies Target PreF-Specific Epitopes

The antibodies were next tested for neutralizing activity against RSV subtypes A and B using a previously described high-throughput neutralization assay (15). Greater than 70% of the isolated antibodies showed neutralizing activity, and approximately 35% -40% neutralized with high potency (IC₅₀≤0.05 μg/ml) (see, e.g., FIG. 4A and FIG. 4B; Table 3). Notably, several clonally unrelated antibodies were ≥5.0-fold more potent than D25 and ≥100-fold more potent than palivizumab (see, e.g., FIG. 4A; Table 3). Interestingly, there was no correlation between neutralization potency and level of SHM, suggesting that extensive SHM is not required for potent neutralization of RSV. Consistent with the binding cross-reactivity data, the majority of neutralizing antibodies showed activity against both subtype A and B (FIG. 4A through FIG. 4C; Table 3).

The relationship between preF- and postF-binding affinity and neutralization potency was next investigated, which clearly demonstrated that the majority of highly potent antibodies bound preferentially or exclusively to preF (see, e.g., FIG. 4D through FIG. 4G; Table 3). Quantifying this difference revealed that more than 80% of highly potent antibodies (IC₅₀<0.05 μg/ml) were specific for preF (See, e.g., FIG. 9; Table 3) and that the median IC₅₀ for preF-specific antibodies was more than 8-fold lower than for pre- and postF cross-reactive antibodies and 80-fold lower than antibodies that specifically recognized postF (see, e.g., FIG. 4E; Table 3). Importantly, there was a positive correlation between preF binding and neutralization (P<0.001, r=0.24), and the apparent preF K_(D)s generally corresponded well with the neutralization IC₅₀s (see, e.g., FIG. 5A; Table 3). In contrast, there was no correlation between neutralization potency and postF affinity (P=0.44, r=-0.07) (see, e.g., FIG. 5B; Table 3). This result is compatible with the occupancy model of antibody-mediated neutralization (47), and suggests that DS-Cav1 is a faithful antigenic mimic of the native preF trimer. Notably, very few antibodies neutralized with IC₅₀s lower than 100 pM, which is consistent with the previously proposed ceiling to affinity maturation (48, 49).

The relationship between neutralization potency and antigenic site was next analyzed. The results, provided in, e.g., FIG. 5C, Table 3, and Table 4, collectively, indicated that over 60% of the highly potent neutralizing antibodies targeted antigenic sites Ø and V, which are two of the three prefusion-F specific sites. In contrast, antibodies targeting sites III and IV showed a wide range of neutralization potencies, and antibodies targeting sites I and II were generally moderate to non-neutralizing. Similar results were obtained using binding affinities and neutralization potencies measured for subtype B (See, e.g., FIG. 10A through FIG. 10C; Table 3 and Table 4). Interestingly, a subset of site IV-directed antibodies neutralized with substantially lower potency than would be expected based on preF binding affinity (see, e.g., FIG. 5A; Table 3). This result may suggest that certain epitopes within site IV are less exposed in the context of the native envelope spike expressed on the crowded surface of the virion than on recombinant preF.

Several Antibodies Cross-Neutralize RSV and HMPV

Given that the RSV and human metapneumovirus (HMPV) F proteins share 33% amino acid identity, and certain RSV F-specific antibodies cross-neutralize HMPV (17, 50), the antibodies from this donor were tested for neutralizing activity against HMPV. Of the 133 antibodies tested, one neutralized HMPV (see, e.g., Table 5). Sequence analysis revealed that this antibody represents the VH1-46 germline gene and contains a significant degree of somatic hypermutation (See, e.g., Table 2 and sequence listing). This cross-neutralizing antibody bound to both the preF and PostF and competed with MPE8 (See, e.g., Table 5), in agreement with previous studies indicating that MPE8 cross-neutralizes four pneumoviruses, including RSV and HMPV (17). This result suggests, inter alia, that highly conserved epitopes are relatively immunogenic in the context of natural RSV and/or HMPV infection.

Affinity Maturation of RSV F-Specific Antibodies:

Some embodiments refer to affinity matured antibodies of any of the antibodies listed in Table 6 (each understood as a “parent” antibody” for producing an affinity matured variant). Affinity matured antibodies may be produced by mutagenesis of any one or more of the CDRs of the parent antibody. According to a specific embodiment, the invention provides for affinity matured variants comprising one or more point mutations e.g., 0, 1, 2, or 3 point mutations in each of the CDR sequences, of any of the antibodies listed in Table 6, or of an antibody comprising the six CDR sequences of any of the antibodies listed in Table 6. Affinity matured variants can be produced by any affinity maturation method employing standard mutagenesis techniques, e.g., for optimizing the binding characteristics, such as increasing affinity of binding, or increasing Kon, or decreasing Koff, and can be characterized by a K_(D) difference of at least 2 fold, 5 fold, 1 log, or 2 logs, or 3 logs, as compared to the parent antibody. Such affinity matured antibodies still have the same binding specificity as the parent antibody and e.g., an optimized affinity of binding the target epitope.

Selected anti RSV antibodies were identified for affinity maturation. Oligos were ordered which comprised CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences that were variegated via NNK diversity. The NNK oligos were incorporated into the parent HC or LC via DNA shuffling, as described previously (Stemmer WP et al., DNA shuffling by random fragmentation and reassembly: In vitro recombination for molecular evolution. Proc Natl Acad Sci USA. Oct. 25 1994 ; 91(22):10747-51). The library was then created by transforming the VH and VL PCR products into yeast already containing either the light chain or heavy chain plasmid of the parent. The diversified libraries were then selected using flow cytometry. For each FACS round, the libraries were affinity pressured using decreasing amounts of antigen and clones with improved binding affinities were sorted and propagated. Once improved binding populations were observed by flow cytometry (typically two rounds of selection), single yeast clones were be picked for sequencing and characterization (Table 6).

A specific embodiment refers to affinity matured variants of the antibody 267 in Table 6. Notably, each of the antibodies numbered 365-372 is an affinity matured variant of the antibody numbered 267 in Table 6.

Antibody Production and Purification of Affinity Matured Antibodies

Yeast clones were grown to saturation and then induced for 48 h at 30° C. with shaking. After induction, yeast cells were pelleted and the supernatants were harvested for purification. IgGs were purified using a Protein A column and eluted with acetic acid, pH 2.0. Fab fragments were generated by papain digestion and purified over KappaSelect (GE Healthcare LifeSciences).

RSV In Vitro Neutralization in ELISA Based Microneutralization Assays

In vitro RSV neutralization was tested in ELISA based Microneutralization Assays using RSV-A strain A2 (ATCC, VR1540P). Virus (at a final multiplicity of infection of approximately 0.25) was added to 96-well plates containing serially diluted mAbs in serum-free MEM and pre-incubated for 30 min at 4° C. Freshly trypsinized Hep-2 cells (1.5×10 E⁴ cells/well) were then added to each well in MEM supplemented with 5% FCS. Following incubation for 4 days at 37° C. and 5% CO₂, medium was aspirated and cells were washed twice with 200 μl PBS/well, air-dried and fixed with 100 μl Acetone (80%). RSV replication was measured by quantification of expressed viral proteins by ELISA. For this purpose, fixed cells were washed 2× times with PBS-0.1% Tween-20, blocked with 1% skimmed milk in PBS for 1 hour at RT and then stained with a polyclonal goat-anti RSV antibody preparation (BioRad, #7950-0004) for 1 hour at RT in blocking buffer. A donkey anti-goat IgG HRP conjugate was used as detection reagent and 1 step-Ultra TMB (Thermo Fisher Scientific, #34209) as substrate. % inhibition of virus replication was calculated relative to control cells infected with virus in absence of neutralizing antibodies. An isotype matched control mAb was included in all experiments. mAb potency is expressed as half-maximal inhibitory concentration that resulted in 50% reduction in virus replication (IC₅₀). Results are provided in FIG. 11 and demonstrate that all mAbs were able to neutralize RSV-A2 in this setting, with a broad range of IC₅₀ values.

Discussion

An in-depth understanding of the human antibody response to RSV infection will aid the development and evaluation of RSV vaccine and therapeutic and/or prophylactic antibody candidates for the treatment and/or prevention of RSV infection. Although previous studies have coarsely mapped the epitopes targeted by RSV-specific neutralizing antibodies in human sera (4, 8), the specificities and functional properties of antibodies induced by natural RSV infection have remained largely undefined. As disclosed herein, preF- and postF-stabilized proteins (11, 15), a high-throughput antibody isolation platform, and a structure-guided collection of prefusion F mutants, were used to clonally dissect the human memory B cell response to RSV F in a naturally infected adult donor, and highly potent and selective RSV-neutralizing—as well as highly potent anti-RSV/anti-HMPV cross-selective and cross-neutralizing—were isolated and characterized.

In the repertoire analyzed, the ratio of preF-specific antibodies to those that recognize both pre- and postF was slightly greater than 1:1 (See, e.g., FIG. 2B). These values are somewhat lower than those reported for human sera, which showed approximately 70% of anti-F serum binding is specific for preF (8). This discrepancy may be the result of differences between the levels of individual antibodies in serum, differences in the B cell phenotypes achieved for a particular specificity, or variation between donors. Despite these minor differences, the results of both studies suggest that preF-specific epitopes and epitopes shared by pre- and postF are immunogenic during natural RSV infection, whereas the unique surfaces on postF are significantly less immunogenic.

The repertoire analysis disclosed herein revealed that the large majority of RSV F-specific antibodies target six dominant antigenic sites on prefusion RSV F: Ø, I, II, III, IV, and V. These sites were defined based on previously determined structures, epitope binning/competition assays, resistance mutations, and secondary structure elements of the preF protein. It is important to note that the nomenclature for describing RSV F antigenic sites has evolved over time (6, 51-57), and previous mapping efforts were based on the postfusion conformation of F and did not include surfaces present exclusively on preF. The crystal structure of preF has provided critical information about F structure and function as well as new reagents to map antibody binding sites on the unique surfaces of preF and surfaces shared with postF. To a first approximation, each antibody can be assigned primarily to one of these sites. However, it is likely that antibody epitopes cover the entire surface of F and that there are antibodies that bind two or more adjacent antigenic sites within a protomer and quaternary antibodies that bind across protomers.

Importantly, the results disclosed herein show that the most potently neutralizing antibodies target antigenic sites Ø and V, both of which are located near the apex of the preF trimer. These findings are consistent with results obtained from human sera mapping, which determined that the majority of neutralizing activity can be removed by pre-incubation with preF (4, 8) and that preF-specific sites other than site Ø make up a considerable fraction of preF-specific neutralizing antibodies (8). Although antigenic site Ø has been shown to be a target of potently neutralizing antibodies (8, 10), the interaction of antibodies with site V is less well understood. Interestingly, it was found that the majority of site V-directed antibodies share several convergent sequence features, suggesting that it may be possible to rapidly detect these types of antibodies in human samples using high-throughput sequencing technology (58). Applicant anticipates this finding to be particularly advantageous in profiling antibody responses to RSV vaccine candidates that aim to preserve the apex of the preF trimer.

The extensive panel of antibodies described here provides new opportunities for passive prophylaxis, as well as for treatment of RSV infection. A large number of these antibodies neutralize RSV more potently than D25, which serves as the basis for MEDI8897—a monoclonal antibody that is currently in clinical trials for the prevention of RSV in young, at risk children (59). Additionally, a sub-set of these antibodies were demonstrated to cross-neutralize HMPV.

The development of an effective RSV vaccine has presented a number of unique challenges, and selection of the optimal vaccination strategy will be of the utmost importance. The in-depth analysis of the human antibody response to natural RSV infection presented here provides insights for the development of such a vaccine. Importantly, the results suggest that immunization of pre-immune donors with preF immunogens would be expected to boost neutralizing responses, whereas the use of postF immunogens would likely expand B cell clones with moderate or weak neutralizing activity. Similarly, immunization of RSV naïve infants with preF immunogens would be expected to activate naïve B cells targeting epitopes associated with substantially more potent neutralizing activity compared to postF immunogens. In addition, the ideal RSV vaccine should preserve antigenic sites Ø and V, since these sites are targeted by the most highly potent antibodies elicited in response to natural RSV infection.

Accordingly, disclosed herein are highly selective and potent anti-RSV antibodies, as well as highly potent cross-neutralizing anti-RSV and anti-HMPV antibodies, as well as vaccine candidates, for the treatment and or prophylaxis of RSV and/or HMPV infection. Additionally, the reagents disclosed here provide a useful set of tools for the evaluation of clinical trials, which will be critical for selecting the optimal RSV vaccination or antibody-based therapeutic strategy from the many currently under investigation (60).

TABLE 1 Antigenic sites targeted by prototypic RSV antibodies Antigenic site Prototypic antibodies Ø D25, 5C4, AM22 (10, 16) I 131-2a, 2F II 1129, palivizumab, motavisumab (6) III MPE8 (17) IV 101F (57), mAb 19 (19)

TABLE 2 Germline usage and sequence information of anti-RSV antibodies LC Number of Number of Antibody VH germline nucleotide nucleotide number germline gene CDR H3 CDR L3 Lineage substitutions substitutions Name (Ab #) gene usage usage Sequence Sequence number in VH in VL ADI- 232 VH4-34 VK1-39 AGTNYGEV QQSYS 4 10 8 18875 NTSNQYFFG TPLT MDV ADI- 233 VH4-304 VK3-20 ARDVGTLVL QQYGS 44 12 4 18876 PTVAYYYG SPLVT MDV ADI- 234 VH1-18 VK2-30 ARESGATAA MQAIH 52 9 8 18877 AMFDY WPRT ADI- 235 VH4-304 VK3-20 ARDGGYDH QQYGA 23 12 6 18878 VWGTHRYF SPWT DK ADI- 236 VH1-18 VK2-30 ARDVPGHG MQGTH 46 9 12 18879 AAFMDV WPPA ADI- 237 VH1-18 VK2-30 ARDPPAYAA MQGTH 36 8 7 18880 TLMDV WPPT ADI- 238 VH1-69 VK3-20 ARDAYEVW QQYGS 21 19 9 18882 TGSYLPPFD SFLT Y ADI- 239 VH1-69 VK1-12 ARVPESLVA QQGTS 79 30 6 18883 SNAYAV FPFT ADI- 240 VH1-3 VK2-28 ARGQIVVIP MQTLQ 57 8 1 18884 RANFWFDP TPIT ADI- 241 VH4-304 VK3-20 ARDGGYDHI QQYGT 22 13 8 18885 WGTHRYFA SPWT L ADI- 242 VH1-69 VK1-9 ARVFFGTCG QQLHS 76 20 8 18887 GASCFPSDL DFQT ADI- 243 VH3-33 VK3-20 ARDHASTPY QQYGS 24 8 10 18888 YMDV FPWT ADI- 244 VH4-34 VK1-39 AGTNVGFV QQSYS 3 25 12 18889 NTHYYFGM VPLT DV ADI- 245 VH1-69 VK3-20 ARDAYEVW QQYGS 21 27 10 18890 TGSYLPPFD SFLT Y ADI- 246 VH1-69 VK3-20 ARDAYEVW QQYGS 21 22 10 18891 TGSYLPPFD SFLT Y ADI- 247 VH1-18 VK2-30 ARDSFSLTG MQATQ 39 7 1 18892 AGFPDY WPRT ADI- 248 VH3-21 VL1-40 ARLGYGGN QSYDL 61 8 3 18893 PELDY SLSSSR V ADI- 249 VH3-30 VL1-40 ARGASYYY QSYDS 54 11 5 18894 VSSDLGY LSASW V ADI- 250 VH5-51 VK1-33 ASVMLRGIM QPYDN 84 12 1 18895 LPPPLT ADI- 251 VH3-30 VK3-15 ARAPYDIWS QQYSI 16 10 6 18896 GYCLDY WPQT ADI- 252 VH3-7 VK4-1 ARDTPDVLR QQYYS 42 11 8 18897 HLEWPPVG SPQT AFDI ADI- 253 VH1-18 VK2-30 ARESGATAA MQAIH 52 9 8 18898 AMFDY WPRT ADI- 254 VH3-30 VK3-15 ARAPYDIWS QQYSI 16 10 6 18899 GYCLDY WPQT ADI- 255 VH3-23 VK1-5 ARDQEVELI QQYYT 38 22 7 18900 DDAFDF YYS ADI- 256 VH1-2 VL1-51 ARSSLVGAS GTWDA 72 18 8 18901 PNFDF SLSAA MV ADI- 257 VH4-59 VL3-21 ARSTWDYG QVWDS 73 8 7 18902 DHFPFDY SPDHPY V ADI- 258 VH1-18 VK2-30 ARDVPGHG MQGTH 46 9 12 18903 AAFMDV WPPA ADI- 259 VH1-18 VK2-30 ARDPPAYAA MQGTH 36 8 7 18904 TLMDV WPPT ADI- 260 VH4-39 VK1-5 ACKRADAD QQYHV 1 29 2 18905 DVDYVAGL YFPLT TGFPWYFDV ADI- 261 VH3-33 VK3-20 ARDHASTPY QQYGS 24 8 10 18906 YMDV FPWT ADI- 262 VH1-69 VK3-11 ARGCCGAV QQRTT 55 21 7 18907 AGFQH GVT ADI- 263 VH3-21 VL1-40 VRGVLPGGT QSYDY 98 16 7 18908 GGGWFDS SLNWV ADI- 264 VH4-304 VK3-20 ARDLGKPL QVYSSS 27 13 9 18909 WDGHYYYG PPIT VDV ADI- 265 VH1-69 VK2-28 ARTAALGPP MQTLQ 74 8 3 18910 GTIVGYMD TPWT V ADI- 266 VH5-51 VK1-33 ARLGIGAAA LQFDN 60 12 7 18911 RNY LPPT ADI- 267 VH3-21 VL1-40 ARDLLPVER QSYDS 31 6 3 18912 GPAFDI RLGGS V ADI- 268 VH5-51 VK1-39 ARQIGGLVC QQSDT 67 13 6 18913 SSESCYFYG TPFT MDV ADI- 269 VH3-15 VL1-40 ATDSRRLYD QSYDD 86 4 3 18915 SRGFYSSAF SLTGW DV V ADI- 270 VH5-51 VK1-39 ARQIGGLVC QQSDT 67 13 6 18916 SSESCYFYG TPFT MDV ADI- 271 VH3-21 VL1-40 VRGVLPGDT QSYDY 98 16 7 18917 GGGWFDS SLNWV ADI- 272 VH5-51 VK3-15 ARLPVGSYY QQYNN 62 8 13 18918 YFNL WLSWT ADI- 273 VH4-31 VK2-28 ARTSYAGR MQGLQ 75 22 4 18919 MLDR IPWT ADI- 274 VH3-30 VL1-51 AKVRNEAW GTWDT 12 10 14 18920 ELLGDALDV SLRAG V ADI- 275 VH1-24 VK1-39 ATPTPVGAT QQSYII 88 15 2 18921 DY PYT ADI- 276 VH4-b VK3-15 ASRRGSGWF QQYNN 83 22 8 18922 FDS WPPGG T ADI- 277 VH3-21 VL1-40 ARDWPNSSS QSYDSS 48 0 0 18923 SPNWFDP LSGFY V ADI- 278 VH5-51 VL1-40 ARCSLSCDY QSYDSS 18 9 11 18924 YGVNL LSGFY V ADI- 279 VH3-30 VK3-11 AKPIVGPTT QQRSN 9 8 0 18925 GYFDY WYT ADI- 280 VH1-18 VK2-30 ARDPPASAA MQGTH 36 19 8 18926 AMLDY GRGIS ADI- 281 VH1-2 VK1-13 ASQSSPYTP QQSFTP 82 21 21 18927 GALDV QFT ADI- 282 VH1-69 VL7-46 ARDIEWFVL LLSYSG 25 15 8 18928 MDPITSYYP ARPV MDV ADI- 283 VH3-11 VL1-44 ARDAVIVVG AAWDD 19 9 6 18929 PVAVHYQY SLNGP YADV V ADI- 284 VH1-69 VK3-20 ARDAYEVW QQYGS 21 14 8 18930 TGSYLPPFD SFLT Y ADI- 285 VH3-49 VK3-15 TRDDILTGF QQYDN 92 6 6 18931 YDRSYYYGI WPPYT HV ADI- 286 VH4-304 VK3-11 ARDLGTLAF QQRST 29 25 10 18932 DPYYYYGID WPT V ADI- 287 VH1-46 VK1-39 ARRGYPDSG QQSYIR 69 26 10 18933 SYPLDY PIT ADI- 288 VH4-304 VK3-11 ARDLGYSSS QQRSN 30 19 6 18935 SPAFYYGID GVLT F ADI- 289 VH1-8 VK1-39 ASQSSPYTP QLNSG 82 26 12 18936 GAMGV ALFT ADI- 290 VH4-304 VK3-20 ARDVGVYS QQYGG 45 25 10 18937 GYDVFHYY SPPVT GMDV ADI- 291 VH3-74 VK1-5 ARDLWTTSP QQYNS 32 15 10 18938 YFDL WA ADI- 292 VH4-34 VK1-39 AGTNYGEV QQSYS 4 3 7 18939 NTSNQYFFG APLT MDV ADI- 293 VH1-8 VK1-39 ASQSSPYTP QLNSG 82 33 14 18940 GAMDV ALFT ADI- 294 VH5-51 VK3-15 GQAVAGGE QHYNN 90 7 5 18941 YFHH WPRG ADI- 295 VH4-304 VK3-11 ARDLGTAN QQRSN 28 19 6 18942 NYYFGMDV WPPYT ADI- 296 VH4-b VK3-20 AGAFWEVW QQYSSS 2 38 7 18943 TGLYSPPFD PLT F ADI- 297 VH1-18 VK2-30 ARDPAVDAI MQGTH 34 20 8 18944 PMLDY WPLT ADI- 298 VH3-30 VL2-14 AKEEWLVP SSYSTN 7 8 3 18946 AY SAP ADI- 299 VH3-30 VK3-15 ARAPYDIWS QQYSI 16 16 7 18947 GYCLDY WPQT ADI- 300 VH3-30 VK3-15 ARAPYDIWS QQYSI 16 13 7 18948 GYCLDY WPQT ADI- 301 VH1-18 VK2-30 ARDPAVDAI MQGTH 34 20 8 18949 PMLDY WPLT ADI- 302 VH4-39 VK3-11 ATAWTFDH QLRGH 85 13 2 18950 WPPTIT ADI- 303 VH3-23 VL2-14 AKDGLRDV SSYRN 5 19 16 18951 SRVYYIDV GNALG V ADI- 304 VH3-23 VL2-14 AKDGLRDLS SSYRN 5 18 11 18952 RVYYIDV GNTLG V ADI- 305 VH1-69 VK3-20 ARDAYEVW QQYGS 21 12 11 18953 TGSYLPPFD SFLT Y ADI- 306 VH3-30 VK3-15 ARAPYDIWS QQYSI 16 11 6 18955 GYCLDY WPQT ADI- 307 VH1-69 VL2-11 ATRLYTLGS CSYAG 89 23 10 18956 PFDN RYIYV ADI- 308 VH3-21 VL1-40 ARVHVDLV QSYDSS 78 12 3 18957 TTIFGVDFDF LSGAI ADI- 309 VH1-18 VK2-30 AREPPSDDA MQGTQ 51 18 3 18958 ARLFDY WPVT ADI- 310 VH1-24 VK1-39 ATPTPVGAT QQTYII 88 18 4 18959 DF PYT ADI- 311 VH4-39 VL3-21 AREGPNWE QVWDT 50 15 5 18960 LLNAFDI SSDHV N ADI- 312 VH3-21 VL1-40 ARVSTELGY QSYDSS 80 1 0 18962 YYMDV LSVV ADI- 313 VH1-3 VK4-1 GRDWDGAI QQYYG 91 14 9 18965 RVLDY NFPT ADI- 314 VH3-30 VK2-30 ARDPGVGSY MQGTH 35 13 3 18966 YNVVGMDV WPPT ADI- 315 VH1-24 VK1-39 ATPLPAGAL QQTYII 88 23 12 18967 DK PYT ADI- 316 VH4-304 VK3-11 TRDLGYSTS QQRTN 93 17 8 18968 SPSFYYGMD WPIT V ADI- 317 VH1-18 VK2-30 ARDVFSKTA MQATD 43 15 4 18969 ARIFDY WPVT ADI- 318 VH4-304 VK3-11 ARDIGYGDH QQRTN 26 6 9 18970 GTGSYYYGI WIT ED ADI- 319 VH3-23 VL3-21 AKDRVGWF QVWDS 6 17 12 18971 GEFDAFDF RSEHVI ADI- 320 VH1-18 VK2-30 ARDPAVDAI MQGTH 34 20 8 18972 PMLDY WPLT ADI- 321 VH2-70 VK3-20 ALMRPFWS QLYHR 13 18 14 18973 RDDYYYSIA SPGSAS V QTVWT ADI- 322 VH1-18 VK2-30 ARDTPATAA MQGIF 41 22 5 18974 PLLDY RPGT ADI- 323 VH1-18 VK2-24 ARDSGCCSG MQATE 40 11 3 18975 STSDV FPPMY T ADI- 324 VH4-31 VK1-39 ARDNKHHD QQSYT 33 5 9 18976 SGNYYAYF TRLT DH ADI- 325 VH1-3 VK1-33 ARQVSTSG QQYDN 68 17 6 18977 WHATSHRF LPLT AP ADI- 326 VH3-30 VK1-5 AKSSSSHVN QQYYN 11 9 11 18978 SRQDK WWT ADI- 327 VH1-18 VK2-30 ARDSFSETG MQATH 39 11 1 18979 TGFPDF RPRT ADI- 328 VH5-51 VK3-11 AKSNVGNT QEVRN 10 8 9 18980 GWNY WPPCT ADI- 329 VH4-30 VK3-20 ARCGNEYG QQYGS 17 27 9 18981 EVHPFDI SPWT ADI- 330 VH1-18 VK2-30 ARDSFSETG MQATH 39 7 1 18982 TGFPDF RPRT ADI- 331 VH3-30 VK1-17 AREAYEEW LQHNR 49 14 5 18983 ELTMGNLD YPFT H ADI- 332 VH4-61 VK1-12 ARGEHFAY QQANS 56 29 5 18984 WWGN FPRT ADI- 333 VH1-2 VK1-39 TSQTSPYTP QQTYN 95 22 16 18985 GAMGV GLIA ADI- 334 VH3-30 VL1-40 ARGASYYY QSYDS 54 12 5 18986 VSSDLGY LSASW V ADI- 335 VH1-69 VK3-20 ARDAYEVW QQYGS 20 12 8 18987 TGSYLPPFD SFLT D ADI- 336 VH3-21 VL1-40 VREAYASSS QSYDSS 97 22 6 18988 ALYWFDP LSGWV ADI- 337 VH3-48 VK2-28 ARSLGSGNY MQALQ 71 14 6 18989 DNEDQTFYY TPYT YYGMDV ADI- 338 VH4-304 VK3-11 ARDLGTAN QQRSN 28 19 6 18990 NYYFGMDV WPPYT ADI- 339 VH4-304 VL3-21 ASGPVGMA QVWDS 81 22 14 18991 TSNWFDP STDYH VV ADI- 340 VH1-46 VL1-40 ARAPSHDE QSYDSS 15 14 7 18992 WVAISRNVV LSAWV GFDA ADI- 341 VH3-21 VL1-40 AREVLPATA QSYDIS 53 10 7 18993 IGGAWLDP LSASY V ADI- 342 VH1-18 VL2-23 ARIGHVTAV CSYVA 58 13 7 18994 AGAPPDY GSTSV ADI- 343 VH4-304 VL3-21 ASGPVGMA QVWDS 81 18 12 18995 TSNWFDP GTDYH VV ADI- 344 VH1-2 VL1-51 ARSSLVGAS GTWDA 72 17 10 18996 PNFDF SLSAA MV ADI- 345 VH4-34 VK3-15 ARVHPSYDF QQYAY 77 16 9 18997 GWRFFDF WPPYT ADI- 346 VH4-304 VL3-21 ASGPVGMA QVWDS 81 15 15 18998 TSNWFDP STDHH VV ADI- 347 VH1-69 VL2-11 ARPNYDILT CSYAG 65 13 3 18999 GYAFDI GLYV ADI- 348 VH1-8 VL1-36 VQMDHCRS AAWDD 96 10 6 19000 TSCSEGNWF SLNVW DT V ADI- 349 VH3-49 VL2-8 TRQDDFWS SSYAGS 94 10 7 19001 GHPYYFEY NDLGV ADI- 350 VH4-59 VK1-39 ARQFGYDK QQSYSI 66 17 8 19002 NTLSRLDFD PWT Y ADI- 351 VH4-39 VL3-21 AREGPNWE QVWDT 50 15 4 19003 LLNAFDI SSDHV V ADI- 352 VH1-18 VK2-30 ARDPPASAA MQGTH 36 19 7 19004 AMLDY GRGIS ADI- 353 VH1-18 VK1-39 ASQSSPYTP QLNSG 82 21 9 19005 GAMGV ALFT ADI- 354 VH3-11 VK3-20 ARAKTSYYF QRYGN 14 30 12 19006 YALDV SWP ADI- 355 VH3-23 VK4-1 AKESLDFGS HQYYD 8 18 5 19007 GSYNWFDT THT ADI- 356 VH3-30 VK3-11 ARDPSLGYN QQRSN 37 15 6 19008 NHYFDY WPPMY S ADI- 357 VH1-69 VK3-20 ARDAYEVW QQYGS 21 19 6 19009 TGSYLPPFD SFLT Y ADI- 358 VH3-21 VL1-40 ARDVQYSG QSYDSS 47 0 0 19010 YDSGYYFD LSALY Y V ADI- 359 VH3-30 VL4-60 ATIRGIVAG EAWDF 87 19 9 19011 LCDN NTGGV ADI- 360 VH4-4 VK1-39 ARLSGNCSG QQSYN 63 12 10 19012 GSCYSPFDH TVYT ADI- 361 VH5-51 VK1-12 ARPMTTQEG QQTNS 64 4 2 19013 FDL FLPLT ADI- 362 VH4-304 VK3-20 ARSADIDIV QQYGT 70 21 10 19014 WGSSLYMP SPWT L ADI- 363 VH3-21 VL1-40 ARIGYSSAH QSYDK 59 13 5 19016 HYQYYMDV SLSGG YC ADI- 364 VH1-18 VL3-25 ASQSSPYTP QSADSS 82 22 0 19017 GAMGV GTYPV V

TABLE 3 Affinity and Neutralization data for anti-RSV antibodies Neut IC₅₀ Antibody Prefusion Postfusion Prefusion Postfusion (μg/ml) Neut IC₅₀ number subtype A K_(D) subtype A K_(D) subtype B K_(D) subtype B K_(D) subtype (μg/ml) Name (Ab #) (M)* (M)* (M)* (M)* A* subtype B* ADI- 232 7.36E−10 NB 7.64E−10 NB 0.040 0.035 18875 ADI- 233 7.07E−10 1.71E−09 3.16E−10 1.79E−10 0.037 0.179 18876 ADI- 234 3.03E−10 NB 3.83E−10 NB 0.410 0.130 18877 ADI- 235 4.53E−09 4.83E−10 5.82E−09 3.88E−10 >10 8.308 18878 ADI- 236 3.12E−10 NB 3.58E−10 NB 0.041 0.103 18879 ADI- 237 2.55E−10 NB 3.04E−10 NB 0.041 0.055 18880 ADI- 238 4.27E−10 NB 4.76E−10 NB 0.041 0.057 18882 ADI- 239 4.31E−10 NB 5.66E−10 NB 0.041 0.050 18883 ADI- 240 3.38E−10 NB 2.04E−10 NB 0.073 0.239 18884 ADI- 241 2.18E−09 3.84E−10 3.89E−09 3.07E−10 0.376 8.635 18885 ADI- 242 NB 7.43E−10 1.22E−08 5.49E−10 1.110 >10 18887 ADI- 243 NB 2.54E−08 NB 1.16E−09 >10 >10 18888 ADI- 244 5.54E−10 NB 5.87E−10 NB 0.040 0.019 18889 ADI- 245 4.89E−10 NB 4.58E−10 NB 0.041 0.041 18890 ADI- 246 5.34E−10 NB 5.13E−10 NB 0.012 0.026 18891 ADI- 247 2.17E−10 NB 2.53E−10 NB 0.018 0.117 18892 ADI- 248 2.45E−10 NB 2.78E−10 NB 0.123 0.182 18893 ADI- 249 2.54E−09 NB 3.27E−10 NB 0.345 0.123 18894 ADI- 250 NB 2.37E−09 NB 4.86E−10 2.303 >10 18895 ADI- 251 2.27E−09 2.79E−10 1.81E−09 2.70E−10 1.100 4.722 18896 ADI- 252 1.47E−09 2.19E−10 1.53E−09 1.85E−10 0.288 0.762 18897 ADI- 253 3.05E−10 NB 3.25E−10 NB 0.030 0.097 18898 ADI- 254 1.92E−09 2.66E−10 1.59E−09 2.51E−10 0.742 2.700 18899 ADI- 255 1.19E−09 NB 3.31E−10 NB 0.035 0.059 18900 ADI- 256 2.17E−09 NB NB NB 5.646 5.762 18901 ADI- 257 1.07E−10 NB 1.01E−10 NB 0.024 0.150 18902 ADI- 258 3.24E−10 NB 2.72E−10 NB 0.036 0.118 18903 ADI- 259 2.51E−10 NB 2.37E−10 NB 0.018 0.089 18904 ADI- 260 3.38E−09 NB NB NB 0.685 3.676 18905 ADI- 261 NB 2.33E−08 NB 1.10E−09 >10 >10 18906 ADI- 262 1.74E−10 NB 2.04E−10 NB 3.300 >10 18907 ADI- 263 3.02E−10 NB 3.52E−10 NB 0.018 0.095 18908 ADI- 264 5.08E−10 5.81E−10 2.88E−10 2.25E−10 0.110 0.169 18909 ADI- 265 4.67E−09 NB 1.06E−08 NB >10 0.767 18910 ADI- 266 NB 3.53E−10 NB 2.80E−10 0.301 4.853 18911 ADI- 267 2.58E−10 NB 2.86E−10 NB 0.024 0.061 18912 ADI- 268 5.68E−10 NB 4.71E−10 NB <0.01 <0.01 18913 ADI- 269 2.81E−08 NB 4.21E−10 NB 1.199 0.021 18915 ADI- 270 5.85E−10 NB 4.65E−10 NB <0.01 <0.01 18916 ADI- 271 3.56E−10 NB 3.32E−10 NB 0.024 0.091 18917 ADI- 272 NB 5.67E−10 NB 4.09E−10 0.377 4.590 18918 ADI- 273 2.02E−10 NB 1.63E−10 NB 0.123 0.261 18919 ADI- 274 6.78E−10 NB 9.77E−11 NB 0.041 0.049 18920 ADI- 275 5.75E−09 NB NB NB 1.703 1.172 18921 ADI- 276 3.47E−09 3.22E−10 5.27E−09 2.87E−10 >10 5.051 18922 ADI- 277 5.17E−10 NB 1.79E−09 NB 0.078 0.147 18923 ADI- 278 6.48E−09 4.11E−10 NB 3.21E−10 0.572 1.073 18924 ADI- 279 4.99E−09 NB NB NB >10 >10 18925 ADI- 280 2.52E−10 NB 2.50E−10 NB 0.023 0.092 18926 ADI- 281 3.58E−09 NB 2.99E−09 NB 0.022 0.067 18927 ADI- 282 4.49E−10 NB 5.15E−10 NB 0.034 0.062 18928 ADI- 283 1.61E−09 NB NB NB 0.261 0.369 18929 ADI- 284 3.87E−10 NB 3.72E−10 NB 0.013 0.051 18930 ADI- 285 5.65E−10 NB 4.88E−10 NB >10 >10 18931 ADI- 286 9.17E−10 NB 1.39E−09 NB 0.184 0.351 18932 ADI- 287 NB 2.00E−08 NB 6.16E−10 0.075 0.137 18933 ADI- 288 6.60E−10 NB 5.82E−10 NB 0.779 0.355 18935 ADI- 289 3.03E−10 NB 2.98E−10 NB 0.032 0.035 18936 ADI- 290 2.89E−10 NB 2.73E−10 NB 0.084 0.508 18937 ADI- 291 1.65E−10 2.16E−10 1.50E−10 1.68E−10 0.837 4.255 18938 ADI- 292 5.74E−10 NB 5.60E−10 NB 0.018 0.038 18939 ADI- 293 1.12E−09 NB 1.56E−09 NB 0.023 0.063 18940 ADI- 294 NB 1.91E−08 NB 6.45E−10 >10 >10 18941 ADI- 295 8.65E−10 2.81E−10 5.12E−10 2.58E−10 0.374 0.614 18942 ADI- 296 6.46E−10 NB 7.25E−10 NB 0.027 0.043 18943 ADI- 297 3.09E−10 NB 3.37E−10 NB 0.026 0.074 18944 ADI- 298 1.58E−10 2.06E−10 1.57E−10 1.66E−10 0.093 0.227 18946 ADI- 299 2.45E−09 2.96E−10 2.20E−09 2.82E−10 1.299 3.602 18947 ADI- 300 4.55E−09 2.57E−10 2.10E−09 2.47E−10 1.123 4.346 18948 ADI- 301 3.07E−10 NB 3.08E−10 NB 0.040 0.076 18949 ADI- 302 1.13E−09 3.93E−10 4.18E−09 3.85E−10 >10 >10 18950 ADI- 303 7.52E−10 1.29E−09 5.35E−09 1.13E−09 3.398 >10 18951 ADI- 304 7.15E−10 7.29E−10 1.01E−09 6.33E−10 1.589 2.745 18952 ADI- 305 5.13E−10 NB 4.21E−10 NB 0.034 0.022 18953 ADI- 306 5.99E−10 2.56E−10 2.37E−09 2.50E−10 1.933 3.116 18955 ADI- 307 1.82E−10 NB 2.24E−10 NB >10 >10 18956 ADI- 308 4.69E−10 NB 3.24E−10 NB 1.339 6.084 18957 ADI- 309 2.86E−10 NB 3.02E−10 NB 0.587 3.364 18958 ADI- 310 4.68E−09 NB NB NB 7.214 2.258 18959 ADI- 311 1.78E−10 NB 1.83E−10 NB 0.034 0.107 18960 ADI- 312 8.83E−09 NB 2.28E−08 NB 4.439 >10 18962 ADI- 313 NB NB NB 3.023 6.892 18965 ADI- 314 5.78E−10 NB 5.62E−10 NB 0.044 0.130 18966 ADI- 315 8.09E−10 NB NB NB 6.737 3.651 18967 ADI- 316 1.98E−09 4.38E−10 6.02E−10 3.05E−10 0.909 0.541 18968 ADI- 317 3.03E−10 NB 2.97E−10 NB 0.035 0.187 18969 ADI- 318 1.04E−08 6.84E−09 4.45E−10 4.12E−10 >10 0.333 18970 ADI- 319 1.57E−10 NB 1.68E−10 NB 0.039 0.114 18971 ADI- 320 2.98E−10 NB 3.68E−10 NB 0.016 0.107 18972 ADI- 321 3.78E−09 4.95E−10 2.63E−09 3.94E−10 9.605 6.273 18973 ADI- 322 2.53E−10 NB 2.90E−10 NB 0.030 0.105 18974 ADI- 323 2.67E−10 NB 2.98E−10 NB 0.037 0.174 18975 ADI- 324 4.03E−09 2.36E−09 1.24E−09 2.09E−10 6.290 10.600 18976 ADI- 325 7.86E−10 NB 9.66E−10 NB 0.108 0.117 18977 ADI- 326 3.00E−09 NB NB NB >10 >10 18978 ADI- 327 1.89E−10 NB 1.84E−10 NB 0.012 0.031 18979 ADI- 328 NB 5.33E−10 NB 3.50E−10 3.599 >10 18980 ADI- 329 1.53E−09 3.53E−10 1.15E−09 2.80E−10 >10 >10 18981 ADI- 330 1.92E−10 7.65E−10 1.95E−10 7.47E−10 0.018 0.053 18982 ADI- 331 1.71E−09 NB 5.81E−10 NB 0.028 0.075 18983 ADI- 332 1.29E−08 8.03E−10 6.08E−09 6.59E−10 >10 >10 18984 ADI- 333 5.66E−10 NB 1.70E−09 NB 0.034 0.090 18985 ADI- 334 2.68E−09 NB 2.38E−10 NB 0.464 0.123 18986 ADI- 335 4.49E−10 NB 5.24E−10 NB 0.015 0.027 18987 ADI- 336 2.93E−10 NB 3.70E−10 NB 0.089 0.370 18988 ADI- 337 3.51E−09 3.56E−10 3.92E−09 3.77E−10 >10 >10 18989 ADI- 338 8.90E−10 2.94E−10 4.91E−10 2.52E−10 0.580 0.845 18990 ADI- 339 1.35E−10 1.52E−10 0.028 0.228 18991 ADI- 340 7.66E−10 1.53E−09 9.69E−10 9.07E−10 2.546 5.692 18992 ADI- 341 2.55E−10 NB 2.77E−10 NB 0.078 0.128 18993 ADI- 342 3.10E−10 NB 3.31E−10 NB 0.047 0.108 18994 ADI- 343 1.20E−10 1.23E−08 1.27E−10 0.043 0.125 18995 ADI- 344 2.52E−09 NB 3.60E−09 NB >10 >10 18996 ADI- 345 5.01E−09 NB 5.32E−09 NB >10 >10 18997 ADI- 346 1.57E−10 1.24E−08 1.72E−10 NB 0.055 0.458 18998 ADI- 347 5.92E−10 1.67E−10 1.02E−09 1.41E−10 1.805 6.465 18999 ADI- 348 1.10E−10 1.75E−10 1.04E−10 1.28E−10 0.037 0.129 19000 ADI- 349 1.07E−09 1.93E−10 1.06E−09 1.49E−10 >10 3.259 19001 ADI- 350 1.63E−09 NB NB NB 2.886 4.507 19002 ADI- 351 1.61E−10 NB 1.68E−10 NB 0.047 0.125 19003 ADI- 352 2.28E−10 NB 2.73E−10 NB 0.020 0.128 19004 ADI- 353 9.63E−10 NB 9.64E−10 NB 0.041 0.110 19005 ADI- 354 1.75E−09 NB NB NB 4.891 5.059 19006 ADI- 355 6.18E−10 9.69E−10 6.08E−10 4.57E−10 0.208 0.370 19007 ADI- 356 3.63E−09 NB NB NB 8.293 >10 19008 ADI- 357 4.42E−10 NB 4.66E−10 NB 0.062 0.066 19009 ADI- 358 6.04E−09 NB 2.84E−09 NB >10 0.650 19010 ADI- 359 2.15E−09 NB NB NB >10 6.237 19011 ADI- 360 2.89E−09 3.04E−10 1.14E−09 3.14E−10 >10 >10 19012 ADI- 361 NB 1.61E−08 NB 5.83E−10 9.504 >10 19013 ADI- 362 2.82E−09 3.59E−10 2.21E−09 2.77E−10 1.745 >10 19014 ADI- 363 NB NB NB NB 0.052 0.092 19016 ADI- 364 1.10E−08 NB 7.20E−09 NB 1.562 0.795 19017 *NN; non-neutralizing, NB; non-binding, ND; not determined. IgG KDs were calculated for antibodies with BLI binding responses with BLI binding responses >0.1 nm. Antibodies with BLI binding responses <0.05 nm were designated as NB.

TABLE 4 Bin, patch, and antigenic site assignments for anti-RSV antibodies Antibody Antigenic number Bin Patch Site Name (Ab #) Assignment Assignment Assignment ADI-18875 232 D25 1, 2 Ø ADI-18876 233 Mota 5 II ADI-18877 234 D25/mota/MPE8 4 V ADI-18878 235 101F/13390 ADI-18879 236 D25/mota/MPE8 4 V ADI-18880 237 D25/mota/MPE8 4 V ADI-18882 238 D25 1, 2 Ø ADI-18883 239 D25 4 V ADI-18884 240 14469 I ADI-18885 241 101F/13390 ADI-18887 242 Mota/13390 ADI-18888 243 Mota/101F/13390 ADI-18889 244 D25 1, 2 Ø ADI-18890 245 D25 2 Ø ADI-18891 246 D25 2, 1 Ø ADI-18892 247 Mota/MPE8 4 V ADI-18893 248 Mota/MPE8 III ADI-18894 249 D25 ADI-18895 250 Unknown ADI-18896 251 101F/13390 ADI-18897 252 Mota/101F/13390 III ADI-18898 253 D25/mota/MPE8 4 V ADI-18899 254 101F/13390 I ADI-18900 255 D25 1 Ø ADI-18901 256 Unknown ADI-18902 257 14443 9 IV ADI-18903 258 D25/mota/MPE8 4, 3 V ADI-18904 259 D25/mota/MPE8 4 V ADI-18905 260 MPE8 ADI-18906 261 Mota/101F/13390 ADI-18907 262 UK ADI-18908 263 Mota/MPE8 III ADI-18909 264 Mota 5 II ADI-18910 265 Unknown ADI-18911 266 Mota ADI-18912 267 Mota/MPE8 III ADI-18913 268 D25 1 Ø ADI-18915 269 D25/mota ADI-18916 270 D25 1 Ø ADI-18917 271 Mota/MPE8 III ADI-18918 272 Mota ADI-18919 273 UK ADI-18920 274 101F 9 IV ADI-18921 275 101F ADI-18922 276 Mota ADI-18923 277 Mota/MPE8/101F III ADI-18924 278 Unknown ADI-18925 279 101F ADI-18926 280 D25/mota/MPE8 4 V ADI-18927 281 D25/mota ADI-18928 282 D25 1, 2 Ø ADI-18929 283 101F 1 UK ADI-18930 284 D25 1, 2 Ø ADI-18931 285 101F IV ADI-18932 286 Mota 5 II ADI-18933 287 Unknown ADI-18935 288 Mota 6, 5 III ADI-18936 289 D25/mota 4 V ADI-18937 290 Mota 5 II ADI-18938 291 Mota/101F III ADI-18939 292 D25 9 Ø ADI-18940 293 D25/mota 1, 2 V ADI-18941 294 Mota ADI-18942 295 Mota II ADI-18943 296 D25 5 UK ADI-18944 297 D25/mota/MPE8 1, 2 V ADI-18946 298 101F 4 IV ADI-18947 299 101F/13390 ADI-18948 300 101F/13390 ADI-18949 301 D25/mota/MPE8 4 V ADI-18950 302 13390 I ADI-18951 303 Mota/13390 III ADI-18952 304 Mota/13390 III ADI-18953 305 D25 2 Ø ADI-18955 306 101F/13390 I ADI-18956 307 14469 I ADI-18957 308 Mota/MPE8 III ADI-18958 309 Mota 4 V ADI-18959 310 14443 ADI-18960 311 14469 9 IV ADI-18962 312 Mota/MPE8 ADI-18965 313 Unknown ADI-18966 314 D25/mota/MPE8 4 V ADI-18967 315 101F 9 IV ADI-18968 316 Mota 5 II ADI-18969 317 D25/mota/MPE8 4 V ADI-18970 318 Mota/MPE8 ADI-18971 319 14469 9 IV ADI-18972 320 D25/mota/MPE8 4 V ADI-18973 321 13390 ADI-18974 322 D25/mota/MPE8 4 V ADI-18975 323 D25/mota/MPE8 4 V ADI-18976 324 13390 ADI-18977 325 D25/mota 4 V ADI-18978 326 14469 ADI-18979 327 Mota/MPE8 4 V ADI-18980 328 Mota ADI-18981 329 101F/13390 I ADI-18982 330 Mota/MPE8 4 V ADI-18983 331 101F 3, 9 Q ADI-18984 332 13390 ADI-18985 333 D25/mota 4 V ADI-18986 334 D25 ADI-18987 335 D25 Ø ADI-18988 336 Mota/MPE8 III ADI-18989 337 101F/13390 ADI-18990 338 Mota 5 II ADI-18991 339 14443 9 IV ADI-18992 340 101F IV ADI-18993 341 Mota/MPE8 III ADI-18994 342 Mota/MPE8 III ADI-18995 343 14443 IV ADI-18996 344 Unknown ADI-18997 345 D25/mota ADI-18998 346 14443 9 IV ADI-18999 347 101F 9 IV ADI-19000 348 14443 9 IV ADI-19001 349 101F/13390 I ADI-19002 350 Unknown UK ADI-19003 351 14469 9 IV ADI-19004 352 D25/mota/MPE8 4 V ADI-19005 353 D25/mota V ADI-19006 354 Unknown UK ADI-19007 355 Mota/MPE8 5 II ADI-19008 356 Unknown ADI-19009 357 D25 1 Ø ADI-19010 358 Mota/MPE8 ADI-19011 359 Unknown ADI-19012 360 13390 ADI-19013 361 Unknown ADI-19014 362 101F/13390 ADI-19016 363 Mota/MPE8 ADI-19017 364 D25/mota

TABLE 5 A subset of anti-RSV F antibodies cross-neutralize human metapneumovirus. Post- Anti- HMPV- RSV- Prefusion fusion RSV F body A1 A2 RSV RSV Bind- number IC₅₀ IC₅₀ F K_(D) F K_(D) ing Name (Ab #) (μg/ml) (μg/ml) (M) (M) Site ADI- 6.1 2.5 7.6 × 1.5 × IV* 18992 10⁻¹⁰ 10⁻⁹ MPE8 N/A 0.07 0.04 — — — Control N/A, not applicable *Binding site assignment based on competition only.

Materials and Methods Study Design

To profile the antibody response to RSV F, peripheral blood mononuclear cells were obtained from a adult donor approximately between 20-35 years of age, and monoclonal antibodies from RSV F-reactive B cells were isolated thereform. The antibodies were characterized by sequencing, binding, epitope mapping, and neutralization assays. All samples for this study were collected with informed consent of volunteers. This study was unblinded and not randomized. At least two independent experiments were performed for each assay.

Generation of RSV F Sorting Probes

The soluble prefusion and postfusion probes were based on the RSV F ΔFP and DS-Cav1 constructs that we previously crystallized and determined to be in the pre- and postfusion conformations, respectively (11, 15). To increase the avidity of the probes and to uniformly orient the RSV F proteins, the trimeric RSV F proteins were coupled to tetrameric streptavidin through biotinylation of a C-terminal AviTag. For each probe, both a C-terminal His-Avi tagged version and a C-terminal StrepTagII version were co-transfected into FreeStyle 293-F cells. The secreted proteins were purified first over Ni-NTA resin to remove trimers lacking the His-Avi tag. The elution from the Ni-NTA purification was then purified over Strep-Tactin resin. Due to the low avidity of a single StrepTagII for the Strep-Tactin resin, additional washing steps were able to remove singly StrepTagged trimers. This resulted in the purification of trimers containing two StrepTagII tagged monomers and therefore only one His-Avi tagged monomer. This purification scheme results in a single AviTag per trimer which greatly reduces the aggregation or ‘daisy-chaining’ that occurs when trimeric proteins containing three AviTags are incubated with tetrameric streptavidin. RSV F trimers were biotinylated using biotin ligase BirA according to the manufacturer's instructions (Avidity, LLC). Biotinylated proteins were separated from excess biotin by size-exclusion chromotography on a Superdex 200 column (GE Healthcare). Quantification of the number of biotin moieties per RSV F trimer was performed using the Quant*Tag Biotin Kit per the manufacturer's instructions (Vector Laboratories).

Single B-Cell Sorting

Peripheral blood mononuclear cells were stained using anti-human IgG (BV605), IgA (FITC), CD27 (BV421), CD8 (PerCP-Cy5.5), CD14 (PerCP-Cy5.5), CD19 (PECy7), CD20 (PECy7) and a mixture of dual-labeled DS-Cav1 and F ΔFP tetramers (50 nM each). Dual-labeled RSV F tetramers were generated by incubating the individual AviTagged RSV F proteins with premium-grade phycoerythrin-labeled streptavidin (Molecular Probes) or premium-grade allophycocyanin-labeled streptavidin for at least 20 minutes on ice at a molar ratio of 4:1. Tetramers were prepared fresh for each experiment. Single cells were sorted on a BD fluorescence-activated cell sorter Aria II into 96-well PCR plates (BioRad) containing 20 μL/well of lysis buffer [5 μL of 5× first strand cDNA buffer (Invitrogen), 0.25 μL RNaseOUT (Invitrogen), 1.25 μL dithiothreitol (Invitrogen), 0.625 μL NP-40 (New England Biolabs), and 12.6 μL dH₂O]. Plates were immediately frozen on dry ice before storage at −80° C.

Amplification and Cloning of Antibody Variable Genes

Single B cell PCR was performed as described previously (22). Briefly, IgH, Igλ and Igκ variable genes were amplified by RT-PCR and nested PCR reactions using cocktails of IgG and IgA-specific primers (22). The primers used in the second round of PCR contained 40 base pairs of 5′ and 3′ homology to the cut expression vectors to allow for cloning by homologous recombination into Saccharomyces cerevisiae (40). PCR products were cloned into S. cerevisiae using the lithium acetate method for chemical transformation (41). Each transformation reaction contained 20 μL of unpurified heavy chain and light chain PCR product and 200 ng of cut heavy and light chain plasmids. Following transformation, individual yeast colonies were picked for sequencing and characterization.

Expression and Purification of IgGs and Fab Fragments

Anti-RSV F IgGs were expressed in S. cerevisiae cultures grown in 24-well plates, as described previously (23). Fab fragments used for competition assays were generated by digesting the IgGs with papain for 2 h at 30° C. The digestion was terminated by the addition of iodoacetamide, and the Fab and Fc mixtures were passed over Protein A agarose to remove Fc fragments and undigested IgG. The flowthrough of the Protein A resin was then passed over CaptureSelect™ IgG-CH1 affinity resin (ThermoFischer Scientific), and eluted with 200 mM acetic acid/50 mM NaCl pH 3.5 into ⅛th volume 2M Hepes pH 8.0. Fab fragments then were buffer-exchanged into PBS pH 7.0.

Biolayer Interferometry Binding Analysis

IgG binding to DS-Cav1 and FΔ FP was determined by BLI measurements using a FortéBio Octet HTX instrument (Pall Life Sciences). For high-throughput K_(D) screening, IgGs were immobilized on AHQ sensors (Pall Life Sciences) and exposed to 100 nM antigen in PBS containing 0.1% BSA (PBSF) for an association step, followed by a dissociation step in PBSF buffer. Data was analyzed using the FortéBio Data Analysis Software 7. The data was fit to a 1:1 binding model to calculate an association and dissociation rate, and K_(D) was calculated using the ratio k_(d)/k_(a).

Antibody Competition Assays

Antibody competition assays were performed as previously described (23). Antibody competition was measured by the ability of a control anti-RSV F Fab to inhibit binding of yeast surface-expressed anti-RSV F IgGs to either DS-Cav1 or FΔ FP. 50 nM biotinylated DS-Cav1 or FΔ FP was pre-incubated with 1 μM competitor Fab for 30 min at room temperature and then added to a suspension of yeast expressing anti-RSV F IgG. Unbound antigen was removed by washing with PBS containing 0.1% BSA (PBSF). After washing, bound antigen was detected using streptavidin Alexa Fluor 633 at a 1:500 dilution (Life Technologies) and analyzed by flow cytometry using a FACSCanto II (BD Biosciences). The level of competition was assessed by measuring the fold reduction in antigen binding in the presence of competitor Fab relative to an antigen-only control. Antibodies were considered competitors when a greater than five-fold reduction was observed in the presence of control Fab relative to an antigen-only control.

Expression, Purification and Biotinylation of PreF Patch Variants

A panel of 9 patches of 2-4 mutations uniformly covering the surface of the preF molecule was designed based on the structure of prefusion RSV F (10). For known antigenic sites, including those recognized by motavizumab, 101F, D25, AM14 and MPE8, patches incorporated residues associated with viral escape or known to be critical for antibody binding. Residues with high conservation across 184 subtype A, subtype B and bovine RSV F sequences were avoided where possible to minimize the likelihood of disrupting protein structure. The mutations present in each patch variant are shown in FIG. 7A. Mutations for each patch variant were cloned into the prefusion stabilized RSV F (DS-Cav1) construct with a C-terminal AviTag for site specific biotinylation. Proteins were secreted from FreeStyle 293-F cells, purified over Ni-NTA resin and biotinylated using biotin ligase BirA according to the manufacturer's instructions (Avidity, LLC). Biotinylated proteins were separated from excess biotin by size-exclusion chromotography on a Superdex 200 column (GE Healthcare). A deglycosylated version of DS-Cav1 was produced by expressing DS-Cav1 in the presence of 1 μM kifunensine and digesting with 10% (wt/wt) EndoH before biotinylation.

Luminex Assay for Patch Variant Binding

Binding of isolated antibodies to the patch variants was determined using a high-throughput Luminex assay. Each biotinylated variant and a DS-Cav1 control were coupled to avidin coated MagPlex beads (Bio-Rad), each with a bead identification number reflecting a unique ratio of red and infrared dyes embedded within the bead. The coupled beads were then mixed with a six-fold serial dilution of each antibody, ranging from 400 nM to 1.4 pM, in a 384-well plate. Beads were washed using a magnetic microplate washer (BioTek) before incubation with a PE conjugated mouse anti-human IgG Fc secondary antibody (Southern Biotech). Beads were classified and binding of PE was measured using a FLEXMAP 3D flow cytometer (Luminex).

RSV Neutralization Assays

Viral stocks were prepared and maintained as previously described (61). Recombinant mKate-RSV expressing prototypic subtype A (strain A2) and subtype B (18537) F genes and the Katushka fluorescent protein were constructed as reported by Hotard et al. (62). HEp-2 cells were maintained in Eagle's minimal essential medium containing 10% fetal bovine serum supplemented with glutamine, penicillin and streptomycin. Antibody neutralization was measured by a fluorescence plate reader neutralization assay (15). A 30 μL solution of culture media containing 2.4×10⁴ HEp-2 cells was seeded in 384-well black optical bottom plate (Nunc, Thermo Scientific). IgG samples were serially diluted four-fold from 1:10 to 1:163840 and an equal volume of recombinant mKate-RSV A2 was added. Samples were mixed and incubated at 37° C. for one hour. After incubation, 50 μL mixture of sample and virus was added to cells in 384-well plate, and incubated at 37° C. for 22-24 hours. The assay plate was then measured for fluorescence intensity in a microplate reader at Ex 588 nm and Em 635 nm (SpectraMax Paradigm, molecular devices). IC₅₀ of neutralization for each sample was calculated by curve fitting using Prism (GraphPad Software Inc.).

Human Metapneuomovirus Neutralization Assays

Predetermined amounts of GFP-expressing hMPV recombinant virus (NL/1/00, A1 sublineage, a kind gift of Bernadette van den Hoogen and Ron Fouchier, Rotterdam, the Netherlands) were mixed with serial dilutions of monoclonal antibodies before being added to cultures of Vero-118 cells growing in 96-well plates with Dulbecco's Modified Eagle's medium supplemented with 10% fetal calf serum. Thirty-six hours later, the medium was removed, PBS was added and the amount of GFP per well was measured with a Tecan microplate reader M200. Fluorescence values were represented as percent of a virus control without antibody.

Polyreactivity Assay

Antibody polyreactivity was assessed using a previously described high-throughput assay that measures binding to solubilized CHO cell membrane preparations (SMPs) (43). Briefly, two million IgG-presenting yeast were transferred into a 96-well assay plate and pelleted to remove the supernatant. The pellet was resuspended in 50 μL of 1:10 diluted stock b-SMPs and incubated on ice for 20 minutes. Cells were then washed twice with ice-cold PBSF and the cell pellet was re-suspended in 50 μL of secondary labeling mix (Extravidin-R-PE, anti-human LCFITC, and propidium iodide). The mix was incubated on ice for 20 minutes followed by two washes with ice-cold PBSF. Cells were then re-suspended in 100 μL of ice-cold PBSF, and the plate was run on a FACSCanto II (BD Biosciences) using a HTS sample injector. Flow cytometry data was analyzed for mean fluorescence intensity in the R-PE channel and normalized to proper controls in order to assess non-specific binding.

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-   An informal sequence listing is provided in Table 6, below. The     informal sequence listing provides the following sixteen (16)     sequence elements contained in each of the 133 antibodies,     identified as described above and designated as Antibody Numbers     (Ab #) 232 through 364, in the following order:     -   Heavy chain variable region (“HC”) nucleic acid sequence     -   Heavy chain variable region (“HC”) amino acid sequence     -   Heavy chain variable region CDR H1 (“H1”) amino acid sequence     -   Heavy chain variable region CDR H1 (“H1”) nucleic acid sequence     -   Heavy chain variable region CDR H2 (“H2”) amino acid sequence     -   Heavy chain variable region CDR H2 (“H2”) nucleic acid sequence     -   Heavy chain variable region CDR H3 (“H3”) amino acid sequence     -   Heavy chain variable region CDR H3 (“H3”) nucleic acid sequence     -   Light chain variable region(“LC”) nucleic acid sequence     -   Light chain variable region (“LC”) amino acid sequence     -   Light chain variable region CDR L1 (“L1”) amino acid sequence     -   Light chain variable region CDR L1 (“L1”) nucleic acid sequence     -   Light chain variable region CDR L2 (“L2”) amino acid sequence     -   Light chain variable region CDR L2 (“L2”) nucleic acid sequence     -   Light chain variable region CDR L3 (“L3”) amino acid sequence     -   Light chain variable region CDR L3 (“L3”) nucleic acid sequence -   The informal sequence listing for antibodies 365-372 provides the     following ten (10) sequence elements contained in each of the 8     antibodies, identified as described above and designated as Antibody     Numbers (Ab #) 365 through 372, in the following order:     -   Heavy chain variable region (“HC”) nucleic acid sequence     -   Heavy chain variable region (“HC”) amino acid sequence     -   Heavy chain variable region CDR H1 (“H1”) amino acid sequence     -   Heavy chain variable region CDR H2 (“H2”) amino acid sequence     -   Heavy chain variable region CDR H3 (“H3”) amino acid sequence     -   Light chain variable region(“LC”) nucleic acid sequence     -   Light chain variable region (“LC”) amino acid sequence     -   Light chain variable region CDR L1 (“L1”) amino acid sequence     -   Light chain variable region CDR L2 (“L2”) amino acid sequence     -   Light chain variable region CDR L3 (“L3”) amino acid sequence

TABLE 6 Informal Sequence Listing Antibody Seq. SEQ ID No. Ref. No. NO. Sequence 232 3697 1 CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGA AGCCTTCGGAGACCCTGTCCCTCACCTGCGCTGTCTAT GGTGGGTCCTTCAGTGGTTATTCCTGGAGCTGGATCCG CCAGACCCCAGGGAAGGGGCTGGAGTGGATTGGGGA AATCAATCATAGAGGAAGCACCAACTACAACCCGTCC CTCAAGAGTCGAGTCACCATGTCAGTGGACACGTCCC AGAACCAGATCTCCCTGAGGGTGACCTCTGTGACCGC CGCGGACACGGCTGTATATTTCTGTGCGGGGACCAAT TATGGAGAGGTTAATACGAGTAACCAGTACTTCTTCG GTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGT CTCCTCA 232 3698 2 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYSWSWIR QTPGKGLEWIGEINHRGSTNYNPSLKSRVTMSVDTSQNQ ISLRVTSVTAADTAVYFCAGTNYGEVNTSNQYFFGMDV WGQGTTVTVSS 232 3699 3 GSFSGYSWS 232 3700 4 GGGTCCTTCAGTGGTTATTCCTGGAGC 232 3701 5 EINHRGSTNYNPSLKS 232 3702 6 GAAATCAATCATAGAGGAAGCACCAACTACAACCCGT CCCTCAAGAGT 232 3703 7 AGTNYGEVNTSNQYFFGMDV 232 3704 8 GCGGGGACCAATTATGGAGAGGTTAATACGAGTAACC AGTACTTCTTCGGTATGGACGTC 232 3705 9 GACATCCAGGTGACCCAGTCTCCATCCTCCCTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCA AGTCAGAGCATTGGCACCTATTTAAATTGGTATCAGC AGAAACCAGGGAAACCCCCTAAACTCCTGATCTATGC TGCATCCAATTTGGAAAGTGGGGTCCCATCAAGTTTC AGTGGCAGTGGATCTGGGACACATTTCACTCTCACCA TCAGCAGTCTGCAACCTGAACATTTTGCAACTTACTAC TGTCAACAGAGTTACAGTACCCCGCTCACTTTCGGCG GAGGGACCAAGGTGGAAATCAAA 232 3706 10 DIQVTQSPSSLSASVGDRVTITCRASQSIGTYLNWYQQKP GKPPKLLIYAASNLESGVPSSFSGSGSGTHFTLTISSLQPE HFATYYCQQSYSTPLTFGGGTKVEIK 232 3707 11 RASQSIGTYLN 232 3708 12 CGGGCAAGTCAGAGCATTGGCACCTATTTAAAT 232 3709 13 AASNLES 232 3710 14 GCTGCATCCAATTTGGAAAGT 232 3711 15 QQSYSTPLT 232 3712 16 CAACAGAGTTACAGTACCCCGCTCACT 233 3713 17 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGA AGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCT GGTCCCTCCATCAGCAGTGGTGATTACTACTGGACTTG GATCCGCCAGCCCCCAGGGAAGGGCCTGGAGTGGATT GGCTACATCTATAACAGTGGGAGCACCGACTACAACC CGTCCCTCAAGAGTCGTATCACCATGTCACTAGACAG GTCCAAGAACCAGTTCTCCCTGAATCTGAGCTCTGTG ACTGCCGCAGACACGGCCGTGTATTTCTGTGCCAGGG ATGTGGGTACTCTGGTACTACCAACTGTTGCTTACTAC TACGGCATGGACGTCTGGGGCCAAGGGACCACGGTCA CCGTCTCCTCA 233 3714 18 QVQLQESGPGLVKPSQTLSLTCTVSGPSISSGDYYWTWI RQPPGKGLEWIGYIYNSGSTDYNPSLKSRITMSLDRSKN QFSLNLSSVTAADTAVYFCARDVGTLVLPTVAYYYGMD VWGQGTTVTVSS 233 3715 19 PSISSGDYYWT 233 3716 20 CCCTCCATCAGCAGTGGTGATTACTACTGGACT 233 3717 21 YIYNSGSTDYNPSLKS 233 3718 22 TACATCTATAACAGTGGGAGCACCGACTACAACCCGT CCCTCAAGAGT 233 3719 23 ARDVGTLVLPTVAYYYGMDV 233 3720 24 GCCAGGGATGTGGGTACTCTGGTACTACCAACTGTTG CTTACTACTACGGCATGGACGTC 233 3721 25 GAAATTGTATTGACGCAGTCTCCAGGCACCCTGTCTTT GTCTCCGGGGGAAAGAGCCACCCTCTCCTGCAGGGCC AGTGAGAGTATTAGCAGCAGCTACTTAGCCTGGTACC AGCAGAAACCTGGCCAGGCTCCCAGACTCCTCATCTA TGATGCGTCCAGCAGGGCCACTGGCATCCCAGACAGG TTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCA CCATCAGCAGTCTGGAGCCTGAAGATTTTGCAGTGTA TTACTGTCAGCAGTATGGTAGCTCACCCCTGGTCACTT TCGGCCCTGGGACCAAAGTGGATATCAAA 233 3722 26 EIVLTQSPGTLSLSPGERATLSCRASESISSSYLAWYQQKP GQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISSLEPE DFAVYYCQQYGSSPLVTFGPGTKVDIK 233 3723 27 RASESISSSYLA 233 3724 28 AGGGCCAGTGAGAGTATTAGCAGCAGCTACTTAGCC 233 3725 29 DASSRAT 233 3726 30 GATGCGTCCAGCAGGGCCACT 233 3727 31 QQYGSSPLVT 233 3728 32 CAGCAGTATGGTAGCTCACCCCTGGTCACT 234 3729 33 CAGGTCCAGCTGGTGCAGTCTGGAACTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCTCCTGTAAGGCTGC TGGTTACACCTTTAGCAACTACGGTGTCAGTTGGGTGC GACAGGCCCCTGGACAGGGGCTTGAGTGGATGGGATG GATCAGCGCTTATAATGGTAACACAAAATTTGCACAG AAGGTCCAGGGCAGACTCACCATGACCACAGACACAT CTACCAGCACAGCCTACATGGAATTGAGGAACCTCAG ATCTGACGACACGGCCGTGTATTATTGTGCGAGAGAA TCAGGGGCAACAGCGGCTGCTATGTTTGACTACTGGG GCCAGGGAACCCTGGTCACCGTCTCCTCA 234 3730 34 QVQLVQSGTEVKKPGASVKVSCKAAGYTFSNYGVSWV RQAPGQGLEWMGWISAYNGNTKFAQKVQGRLTMTTDT STSTAYMELRNLRSDDTAVYYCARESGATAAAMFDYW GQGTLVTVSS 234 3731 35 YTFSNYGVS 234 3732 36 TACACCTTTAGCAACTACGGTGTCAGT 234 3733 37 WISAYNGNTKFAQKVQG 234 3734 38 TGGATCAGCGCTTATAATGGTAACACAAAATTTGCAC AGAAGGTCCAGGGC 234 3735 39 ARESGATAAAMFDY 234 3736 40 GCGAGAGAATCAGGGGCAACAGCGGCTGCTATGTTTG ACTAC 234 3737 41 GAAACGACACTCACGCAGTCTCCACTCTCCCTGCCCG TCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCT AGTCAAAGCCTCGAATACAGTGATGGAAACATCTACT TGAGTTGGTTTCAACAGAGGCCAGGCCAATCTCCAAG GCGCCTAATTTATAAGGTTTCTCACCGGGACTCTGGG GTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTG ATTTCACACTGAAAATCGCCAGGGTGGAGGCTGAGGA TGTTGCAGTTTATTACTGCATGCAAGCTATACACTGGC CTCGAACTTTTGGCCAGGGGACCAAAGTGGATATCAA A 234 3738 42 ETTLTQSPLSLPVTLGQPASISCRSSQSLEYSDGNIYLSWF QQRPGQSPRRLIYKVSHRDSGVPDRFSGSGSGTDFTLKIA RVEAEDVAVYYCMQAIHWPRTFGQGTKVDIK 234 3739 43 RSSQSLEYSDGNIYLS 234 3740 44 AGGTCTAGTCAAAGCCTCGAATACAGTGATGGAAACA TCTACTTGAGT 234 3741 45 KVSHRDS 234 3742 46 AAGGTTTCTCACCGGGACTCT 234 3743 47 MQAIHWPRT 234 3744 48 ATGCAAGCTATACACTGGCCTCGAACT 235 3745 49 CAGGTGCAGCTGCAGGAGTCGGGCCCAAGACTGGTGA AGCCTTCACAGACCCTGTCCCTCATCTGCGATGTCTCT GGTGGCTCCATCGGCAGTGGTGACCACTACTGGAGTT GGATCCGCCAGCCCCCCGGGAAGGGCCTCGAGTGGAT TGGGTACATCTATTACAGTGGGACCACTTACTACAAC CCGTCCCTCAAGAGTCGAGTGACCATTTCAGCAGACA CGTCCAAGAACCAGTTGTCCCTGAAATTGAGTTCTGT GACTGCCGCAGACACGGCCATTTATTTCTGTGCCAGA GATGGGGGTTATGATCACGTCTGGGGGACTCATCGTT ATTTCGACAAGTGGGGCCAGGGAACCCTGGTCACCGT CTCCTCA 235 3746 50 QVQLQESGPRLVKPSQTLSLICDVSGGSIGSGDHYWSWI RQPPGKGLEWIGYIYYSGTTYYNPSLKSRVTISADTSKN QLSLKLSSVTAADTAIYFCARDGGYDHVWGTHRYFDK WGQGTLVTVSS 235 3747 51 GSIGSGDHYWS 235 3748 52 GGCTCCATCGGCAGTGGTGACCACTACTGGAGT 235 3749 53 YIYYSGTTYYNPSLKS 235 3750 54 TACATCTATTACAGTGGGACCACTTACTACAACCCGTC CCTCAAGAGT 235 3751 55 ARDGGYDHVWGTHRYFDK 235 3752 56 GCCAGAGATGGGGGTTATGATCACGTCTGGGGGACTC ATCGTTATTTCGACAAG 235 3753 57 GAAATTGTATTGACACAGTCTCCAGGCACCCTGTCTTT GTCTCCCGGGGAAAGAGCCACCCTCTCCTGCAGGGCC AGTCAGAGTGTTAGCAACAGTTACTTAGCCTGGTACC AGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTA TGGTGTTTCCACCAGGGCCACTGGCATCCCAGACCGG TTCAGTGGCAGCGGGTCTGGGACAGACTTCACCCTCA CCATCAGCAGACTGGAACCTGAAGATTTTGCAATGTA TCACTGTCAGCAGTATGGTGCCTCACCTTGGACGTTCG GCCAAGGGACCAAAGTGGATATCAAA 235 3754 58 EIVLTQSPGTLSLSPGERATLSCRASQSVSNSYLAWYQQ KPGQAPRLLIYGVSTRATGIPDRFSGSGSGTDFTLTISRLE PEDFAMYHCQQYGASPWTFGQGTKVDIK 235 3755 59 RASQSVSNSYLA 235 3756 60 AGGGCCAGTCAGAGTGTTAGCAACAGTTACTTAGCC 235 3757 61 GVSTRAT 235 3758 62 GGTGTTTCCACCAGGGCCACT 235 3759 63 QQYGASPWT 235 3760 64 CAGCAGTATGGTGCCTCACCTTGGACG 236 3761 65 GAGGTGCAGCTGTTGGAGTCTGGAGGTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCTCCTGCAGGGCCTC TGGTTACACCTTTAGAAACTATGGCCTCACCTGGGTGC GGCAGGCCCCCGGACAAGGGCTTGAGTGGATGGGAT GGATCAGCGCTTACAATGGAAACACAAACTATGCACA GAAGTTCCAGGGCAGAGTCACACTGACCACGGACACA TCCACGAGCACAGCCTACATGGAACTGAGGAGCCTAA GATCTGACGACACGGCCGTGTATTTCTGTGCGAGAGA CGTCCCCGGCCACGGCGCTGCCTTCATGGACGTCTGG GGCACAGGGACCACGGTCACCGTCTCCTCA 236 3762 66 EVQLLESGGEVKKPGASVKVSCRASGYTFRNYGLTWVR QAPGQGLEWMGWISAYNGNTNYAQKFQGRVTLTTDTS TSTAYMELRSLRSDDTAVYFCARDVPGHGAAFMDVWG TGTTVTVSS 236 3763 67 YTFRNYGLT 236 3764 68 TACACCTTTAGAAACTATGGCCTCACC 236 3765 69 WISAYNGNTNYAQKFQG 236 3766 70 TGGATCAGCGCTTACAATGGAAACACAAACTATGCAC AGAAGTTCCAGGGC 236 3767 71 ARDVPGHGAAFMDV 236 3768 72 GCGAGAGACGTCCCCGGCCACGGCGCTGCCTTCATGG ACGTC 236 3769 73 GACATCCAGTTGACCCAGTCTCCACTCTCCCTGCCCGT CACCCTTGGGCAGCCGGCCTCCATCTCCTGCAGGTCTA GTCAAAGCCTCGAAGCCAGTGATACAAATATCTACTT GAGTTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGG CGCCTAATTTATAAGATTTCTAACCGAGACTCTGGGGT CCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTCAT TTCACACTGAGAATCAGCAGGGTGGAGGCTGACGATG TTGCGGTTTATTACTGCATGCAGGGTACACACTGGCCT CCGGCGTTCGGCCAGGGGACCAAAGTGGATATCAAA 236 3770 74 DIQLTQSPLSLPVTLGQPASISCRSSQSLEASDTNIYLSWF QQRPGQSPRRLIYKISNRDSGVPDRFSGSGSGTHFTLRISR VEADDVAVYYCMQGTHWPPAFGQGTKVDIK 236 3771 75 RSSQSLEASDTNIYLS 236 3772 76 AGGTCTAGTCAAAGCCTCGAAGCCAGTGATACAAATA TCTACTTGAGT 236 3773 77 KISNRDS 236 3774 78 AAGATTTCTAACCGAGACTCT 236 3775 79 MQGTHWPPA 236 3776 80 ATGCAGGGTACACACTGGCCTCCGGCG 237 3777 81 CAGGTCCAGCTGGTACAGTCTGGATCTGAGGTGAAGA AGCCTGGGGCCGCAGTGAAGGTCTCCTGCAAGGCTTC TGGTTACATCTTTGCCAACTTTGGTGTCAGCTGGGTGC GACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATG GATCAGCGCTTACAATGGTAACACAAACTATGCACAG AAGTTCCAGGGCAGAGTCATCATGACCACAGACACAT CCACGAGCACAGCCTACATGGAGCTGAGGAGCCTGAG ATCTGACGACACGGCCGTGTATTATTGTGCGAGAGAC CCCCCCGCCTACGCCGCTACATTGATGGACGTCTGGG GCAAAGGGACCACGGTCACTGTCTCCTCA 237 3778 82 QVQLVQSGSEVKKPGAAVKVSCKASGYIFANFGVSWVR QAPGQGLEWMGWISAYNGNTNYAQKFQGRVIMTTDTS TSTAYMELRSLRSDDTAVYYCARDPPAYAATLMDVWG KGTTVTVSS 237 3779 83 YIFANFGVS 237 3780 84 TACATCTTTGCCAACTTTGGTGTCAGC 237 3781 85 WISAYNGNTNYAQKFQG 237 3782 86 TGGATCAGCGCTTACAATGGTAACACAAACTATGCAC AGAAGTTCCAGGGC 237 3783 87 ARDPPAYAATLMDV 237 3784 88 GCGAGAGACCCCCCCGCCTACGCCGCTACATTGATGG ACGTC 237 3785 89 GAAATTGTATTGACGCAGTCTCCACTCTCCCTGCCCGT CACCCTTGGACAGTCGGCCTCCATCTCCTGCAGGTCTA GTCAAAGCCTCGAACACAGTGATACAAACACCTACTT GACTTGGTATCAGCAGAGGCCAGGCCAATCTCCAAGG CGGCTACTTTATAAGGTTTCTAACCGGGACTCTGGGGT CCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGAT TTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATG TTGGGGTTTATTACTGCATGCAAGGTACACACTGGCCT CCGACGTTCGGCCAAGGGACCAAAGTGGATATCAAA 237 3786 90 EIVLTQSPLSLPVTLGQSASISCRSSQSLEHSDTNTYLTWY QQRPGQSPRRLLYKVSNRDSGVPDRFSGSGSGTDFTLKIS RVEAEDVGVYYCMQGTHWPPTFGQGTKVDIK 237 3787 91 RSSQSLEHSDTNTYLT 237 3788 92 AGGTCTAGTCAAAGCCTCGAACACAGTGATACAAACA CCTACTTGACT 237 3789 93 KVSNRDS 237 3790 94 AAGGTTTCTAACCGGGACTCT 237 3791 95 MQGTHWPPT 237 3792 96 ATGCAAGGTACACACTGGCCTCCGACG 238 3793 97 CAGGTCCAGCTTGTACAGTCTGGGGCTGAGGTGAAGA AGCCTGGGTCCTCGGTGAGGGTCTCCTGCAAGGCCTC TGGAGGCACCTTCAGGGGCTATGGTCTCAGCTGGGTG CGACAGGCCCCTGGACAGGGACTCGAGTGGATGGGA GGGATCACCCATCTTTTTGGGACAGTCAGCTACGCTCC GAAGTTCCAGGGCAGACTCACGATCACCGCGGACGCA TCCACGGGCACAGCCTACATGGAGCTGAGCAGCCTGA TATCTGAGGACACGGCCGTATATTTTTGTGCGAGAGA TGCTTACGAAGTGTGGACCGGCTCTTATCTCCCCCCTT TTGACTACTGGGGCCAGGGAACAATGGTCACCGTCTC TTCA 238 3794 98 QVQLVQSGAEVKKPGSSVRVSCKASGGTFRGYGLSWVR QAPGQGLEWMGGITHLFGTVSYAPKFQGRLTITADAST GTAYMELSSLISEDTAVYFCARDAYEVWTGSYLPPFDY WGQGTMVTVSS 238 3795 99 GTFRGYGLS 238 3796 100 GGCACCTTCAGGGGCTATGGTCTCAGC 238 3797 101 GITHLFGTVSYAPKFQG 238 3798 102 GGGATCACCCATCTTTTTGGGACAGTCAGCTACGCTCC GAAGTTCCAGGGC 238 3799 103 ARDAYEVWTGSYLPPFDY 238 3800 104 GCGAGAGATGCTTACGAAGTGTGGACCGGCTCTTATC TCCCCCCTTTTGACTAC 238 3801 105 GATATTGTGATGACTCAGTCTCCAGGCACCCTGTCTTT GTCTCCCGGGGAAAGAGTCACCCTCTCCTGCAGGGCC AGTCAGATTATTCCAAGCAGTTACTTAGCCTGGTACC AGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTA TGGTGCATTCACCAGGGCCACTGACATCCCAGACAGG TTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCA CCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTATA TTATTGTCAGCAGTATGGTAGTTCATTTCTCACTTTCG GCGGAGGGACCAAGGTGGAAATCAAA 238 3802 106 DIVMTQSPGTLSLSPGERVTLSCRASQIIPSSYLAWYQQK PGQAPRLLIYGAFTRATDIPDRFSGSGSGTDFTLTISRLEP EDFAVYYCQQYGSSFLTFGGGTKVEIK 238 3803 107 RASQIIPSSYLA 238 3804 108 AGGGCCAGTCAGATTATTCCAAGCAGTTACTTAGCC 238 3805 109 GAFTRAT 238 3806 110 GGTGCATTCACCAGGGCCACT 238 3807 111 QQYGSSFLT 238 3808 112 CAGCAGTATGGTAGTTCATTTCTCACT 239 3809 113 CAGGTCCAGCTTGTGCAGTCTGGGCCTGAGGTAAAGA AGCCTGGGTCCTCAGTGACGGTCTCCTGCAAGGCTTCT GGAGGCACCTTCAGCAACTATGGTATTGCTTGGGTGC GACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATC AACAATCCCTATCCTTGGAACAGCAAGCTACAGACAG AGCTTAAAGGACAGAGTCACAATTACCGCGGACGCTT CCACGACCACAGTCTACATGGAAATGACTCGCCTCAG AACTGAGGACACGGCCGTCTATTTTTGTGCGAGAGTT CCGGAGAGTCTTGTGGCATCAAACGCTTATGCTGTTTG GGGCCAAGGGACGGTGGTCACTGTCTCCTCA 239 3810 114 QVQLVQSGPEVKKPGSSVTVSCKASGGTFSNYGIAWVR QAPGQGLEWMGSTIPILGTASYRQSLKDRVTITADASTT TVYMEMTRLRTEDTAVYFCARVPESLVASNAYAVWGQ GTVVTVSS 239 3811 115 GTFSNYGIA 239 3812 116 GGCACCTTCAGCAACTATGGTATTGCT 239 3813 117 STIPILGTASYRQSLKD 239 3814 118 TCAACAATCCCTATCCTTGGAACAGCAAGCTACAGAC AGAGCTTAAAGGAC 239 3815 119 ARVPESLVASNAYAV 239 3816 120 GCGAGAGTTCCGGAGAGTCTTGTGGCATCAAACGCTT ATGCTGTT 239 3817 121 GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCG AGCCAGGACATTAGCACCTGGTTAGCCTGGTATCAGC AGAGACCAGGGAAAGCCCCAAAACTCCTGATCTACAC TGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTC AGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCA TCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTAT TGTCAACAGGGTACCAGTTTCCCATTCACTTTCGGCCC TGGGACCAAGCTGGAGATCAAA 239 3818 122 DIQMTQSPSSVSASVGDRVTITCRASQDISTWLAWYQQR PGKAPKLLIYTASSLQSGVPSRFSGSGSGTEFTLTISSLQP EDFATYYCQQGTSFPFTFGPGTKLEIK 239 3819 123 RASQDISTWLA 239 3820 124 CGGGCGAGCCAGGACATTAGCACCTGGTTAGCC 239 3821 125 TASSLQS 239 3822 126 ACTGCATCCAGTTTGCAAAGT 239 3823 127 QQGTSFPFT 239 3824 128 CAACAGGGTACCAGTTTCCCATTCACT 240 3825 129 GAGGTGCAGCTGGTGGAGTCTGGGGCTGAGATGAAG AAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCTT CTGGATACACCTTCACTAACTATGCTATACATTGGGTG CGCCAGGCCCCCGGCCAAAGCCTTGAGTGGATGGGAT GGATCAACGCTGGCAATGGTAACACACAATATTCACA GAAGTTCCAGGGCAGAGTCACCTTTACCAGGGACACA TCCGCGAGCACGGTCTACATGGACCTGAGCAGCCTGA GATCTGAAGACACGGCTGTCTATTACTGTGCGAGAGG CCAAATTGTTGTTATACCACGTGCTAATTTCTGGTTCG ACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTC A 240 3826 130 EVQLVESGAEMKKPGASVKVSCKASGYTFTNYAIHWVR QAPGQSLEWMGWINAGNGNTQYSQKFQGRVTFTRDTS ASTVYMDLSSLRSEDTAVYYCARGQIVVIPRANFWFDP WGQGTLVTVSS 240 3827 131 YTFTNYAIH 240 3828 132 TACACCTTCACTAACTATGCTATACAT 240 3829 133 WINAGNGNTQYSQKFQG 240 3830 134 TGGATCAACGCTGGCAATGGTAACACACAATATTCAC AGAAGTTCCAGGGC 240 3831 135 ARGQIVVIPRANFWFDP 240 3832 136 GCGAGAGGCCAAATTGTTGTTATACCACGTGCTAATT TCTGGTTCGACCCC 240 3833 137 GATATTGTGCTGACCCAGTCTCCACTCTCCCTGCCCGT CACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGGTCT AGTCAGAGCCTCCTGCATAGTCATGGATACAACTATT TGGATTGGTACTTGCAGAAGCCAGGGCAGTCTCCACA GCTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGG TCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGA TTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGGAT GTTGGGGTTTATTACTGCATGCAAACTCTACAAACTCC GATCACCTTCGGCCAAGGGACACGAATGGAGATTAAA 240 3834 138 DIVLTQSPLSLPVTPGEPASISCRSSQSLLHSHGYNYLDW YLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKI SRVEAEDVGVYYCMQTLQTPITFGQGTRMEIK 240 3835 139 RSSQSLLHSHGYNYLD 240 3836 140 AGGTCTAGTCAGAGCCTCCTGCATAGTCATGGATACA ACTATTTGGAT 240 3837 141 LGSNRAS 240 3838 142 TTGGGTTCTAATCGGGCCTCC 240 3839 143 MQTLQTPIT 240 3840 144 ATGCAAACTCTACAAACTCCGATCACC 241 3841 145 GAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTG AAGCCTTTACAGACCCTGTCCGTCACCTGCAGTGTCTC TGGTGGCTCCATCAGCAGTGGTGATAACTACTGGAGC TGGATCCGCCAGCGCCCAGGGAAGGGCCTGGAGTGG ATTGGGTACATCTATTACAGTGGGACCACCTACTACA ATCCGTCCCTCAAGAGTCGAGTTACCATATCAGCAGA CAGGTCTAAGAATCAGTTTTCTCTGAAGATGAATTCTC TGAGTGCCGCGGACACGGCCGTGTATTACTGTGCGAG AGATGGCGGATATGATCACATCTGGGGGACTCATCGT TATTTCGCCCTCTGGGGCCAGGGAACCCTGGTCACCG TCTCCTCA 241 3842 146 EVQLQESGPGLVKPLQTLSVTCSVSGGSISSGDNYWSWI RQRPGKGLEWIGYIYYSGTTYYNPSLKSRVTISADRSKN QFSLKMNSLSAADTAVYYCARDGGYDHIWGTHRYFAL WGQGTLVTVSS 241 3843 147 GSISSGDNYWS 241 3844 148 GGCTCCATCAGCAGTGGTGATAACTACTGGAGC 241 3845 149 YIYYSGTTYYNPSLKS 241 3846 150 TACATCTATTACAGTGGGACCACCTACTACAATCCGTC CCTCAAGAGT 241 3847 151 ARDGGYDHIWGTHRYFAL 241 3848 152 GCGAGAGATGGCGGATATGATCACATCTGGGGGACTC ATCGTTATTTCGCCCTC 241 3849 153 GAAACGACACTCACGCAGTCTCCAGGCACCCTGTCTT TGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGC CAGTCAGAGTGTTAACAGCGACTACTTGGCCTGGTAC CAGCAGAAACTTGGCCAGGCTCCCAGGCTCCTCATTT ATGGTGTATCCAACAGGGCCACTGGCATCCCAGACAG GTTTACTGGGAGTGGGTCTGGGACAGACTTCACTCTC ACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTCT ATCACTGTCAGCAGTATGGTACCTCACCGTGGACGTT CGGCCAAGGGACCAAGGTGGAGATCAAA 241 3850 154 ETTLTQSPGTLSLSPGERATLSCRASQSVNSDYLAWYQQ KLGQAPRLLIYGVSNRATGIPDRFTGSGSGTDFTLTISRLE PEDFAVYHCQQYGTSPWTFGQGTKVEIK 241 3851 155 RASQSVNSDYLA 241 3852 156 AGGGCCAGTCAGAGTGTTAACAGCGACTACTTGGCC 241 3853 157 GVSNRAT 241 3854 158 GGTGTATCCAACAGGGCCACT 241 3855 159 QQYGTSPWT 241 3856 160 CAGCAGTATGGTACCTCACCGTGGACG 242 3857 161 CAGGTCCAGCTTGTACAGTCTGGGGCTGAGGTGAAGA GGCCTGGGTCCTCGGTGAAAGTCTCCTGTAAGGCCTC TGGAGGCACCTTCAGTAGTTATGCTCTCTCCTGGGTAC GGCAGGCCCCTGGACAAGGACTTGAGTGGATAGGGG GGATCATCCCTATGCATCGTGTAACAAATTACGCACA GAAATTTCGGGGCAGAGTCACAATTTCCGCGGACACA TCCACGAGTACGGCCTACTTGGAGGTGAACAGCCTGA GAGTTGAGGACACGGCCATGTATTACTGTGCGAGAGT GTTTTTCGGAACTTGTGGCGGTGCTTCGTGCTTCCCCT CTGACCTCTGGGGCCAGGGAACCCTGGTCACTGTCTC CTCA 242 3858 162 QVQLVQSGAEVKRPGSSVKVSCKASGGTFSSYALSWVR QAPGQGLEWIGGIIPMHRVTNYAQKFRGRVTISADTSTS TAYLEVNSLRVEDTAMYYCARVFFGTCGGASCFPSDLW GQGTLVTVSS 242 3859 163 GTFSSYALS 242 3860 164 GGCACCTTCAGTAGTTATGCTCTCTCC 242 3861 165 GIIPMHRVTNYAQKFRG 242 3862 166 GGGATCATCCCTATGCATCGTGTAACAAATTACGCAC AGAAATTTCGGGGC 242 3863 167 ARVFFGTCGGASCFPSDL 242 3864 168 GCGAGAGTGTTTTTCGGAACTTGTGGCGGTGCTTCGTG CTTCCCCTCTGACCTC 242 3865 169 GAAATTGTGTTGACACAGTCTCCATCCTTCGTGTCTGC TTCTGTCGGAGACGGGGTCACCATCACTTGCCGGGCC AGTCAGGCCATTAGCAGTTATTTAGCCTGGTATCAGC AAAAACCAGGGCAAGCCCCTAAACTCCTGATCTATGC TGCATCCACTTTGCAAGGTGGTGTCCCATCAAGGTTCA GCGGCAGTGGATCTGGGACACATTTCACTCTCACCAT CAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACT GTCAGCAACTTCATAGTGATTTTCAGACTTTCGGCCCT GGGACCAAGGTGGAAATCAAA 242 3866 170 EIVLTQSPSFVSASVGDGVTITCRASQAISSYLAWYQQKP GQAPKLLIYAASTLQGGVPSRFSGSGSGTHFTLTISSLQPE DFATYYCQQLHSDFQTFGPGTKVEIK 242 3867 171 RASQAISSYLA 242 3868 172 CGGGCCAGTCAGGCCATTAGCAGTTATTTAGCC 242 3869 173 AASTLQG 242 3870 174 GCTGCATCCACTTTGCAAGGT 242 3871 175 QQLHSDFQT 242 3872 176 CAGCAACTTCATAGTGATTTTCAGACT 243 3873 177 CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCC AGCCTGGGAGGTCCCTGAGACTCTCCTGTGTAGCGTC TGGATTCAGCTTCAGTATGCATGGCATGCACTGGGTC CGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGACA GCTATATGGTATGATGGAAGTAATAAATATTATGCAG ACTCCGTGAAGGGCCGATTCACGATCTCCAGAGACAA TTCTAGGAACACGCTGTATCTGCAAATGAACAGCCTG AGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAG ATCATGCCTCAACTCCATACTACATGGACGTCTGGGG CAAAGGGACCACGGTCACCGTCTCCTCA 243 3874 178 QVQLVESGGGVVQPGRSLRLSCVASGFSFSMHGMHWV RQAPGKGLEWVTAIWYDGSNKYYADSVKGRFTISRDNS RNTLYLQMNSLRAEDTAVYYCARDHASTPYYMDVWG KGTTVTVSS 243 3875 179 FSFSMHGMH 243 3876 180 TTCAGCTTCAGTATGCATGGCATGCAC 243 3877 181 AIWYDGSNKYYADSVKG 243 3878 182 GCTATATGGTATGATGGAAGTAATAAATATTATGCAG ACTCCGTGAAGGGC 243 3879 183 ARDHASTPYYMDV 243 3880 184 GCGAGAGATCATGCCTCAACTCCATACTACATGGACG TC 243 3881 185 GAAACGACACTCACGCAGTCTCCAGGCACCCTGTCTT TGTCTCCAGGGGAAAGCGCCACCCTCTCCTGCAGGAC CAGTCAGAGGATTAGCAGCACCTACTTAGCCTGGTAC CGGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATGT ATGGTGCATCCAGCAGGGCCACTGGCATCCCGGACAG GTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTC ACCATCAGCAGTCTGGAGCCTGAAGATTTTGCACTAT ATTACTGTCAGCAGTATGGTAGCTTTCCGTGGACGTTC GGCCAAGGGACCAAGCTGGAGATCAAA 243 3882 186 ETTLTQSPGTLSLSPGESATLSCRTSQRISSTYLAWYRQK PGQAPRLLMYGASSRATGIPDRFSGSGSGTDFTLTISSLEP EDFALYYCQQYGSFPWTFGQGTKLEIK 243 3883 187 RTSQRISSTYLA 243 3884 188 AGGACCAGTCAGAGGATTAGCAGCACCTACTTAGCC 243 3885 189 GASSRAT 243 3886 190 GGTGCATCCAGCAGGGCCACT 243 3887 191 QQYGSFPWT 243 3888 192 CAGCAGTATGGTAGCTTTCCGTGGACG 244 3889 193 CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTGG AAGCCTTCGCAGACCCTGTCCCTCACCTGCGCTGTCCA TGGTGGATCCCTCAGTGGCTACTCTTGGAGTTGGATCC GCCAGTCCCCAGGGAGGGGACTGGAGTGGATCGGCG AAGTCAATCGTAGGGGAACCACCAACTACAACCCCTC CCTCAAGGGTCGAGTCTCCATATCCTGGGACACGTCC AAGAACCAGGTCTCCCTGTCCCTGAGGTCTGTGACCG CCGCGGACACGGCTACATATTACTGTGCGGGGACCAA TGTTGGATTCGTTAATACCCATAACGACTACTACTTCG GTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGT CTCCTCA 244 3890 194 QVQLQQWGAGLWKPSQTLSLTCAVHGGSLSGYSWSWI RQSPGRGLEWIGEVNRRGTTNYNPSLKGRVSISWDTSKN QVSLSLRSVTAADTATYYCAGTNVGFVNTHNDYYFGM DVWGQGTTVTVSS 244 3891 195 GSLSGYSWS 244 3892 196 GGATCCCTCAGTGGCTACTCTTGGAGT 244 3893 197 EVNRRGTTNYNPSLKG 244 3894 198 GAAGTCAATCGTAGGGGAACCACCAACTACAACCCCT CCCTCAAGGGT 244 3895 199 AGTNVGFVNTHNDYYFGMDV 244 3896 200 GCGGGGACCAATGTTGGATTCGTTAATACCCATAACG ACTACTACTTCGGTATGGACGTC 244 3897 201 GATATTGTGATGACTCAGTCTCCATCCTCCCTGTCTGC ATCGGTTGGAGACAGAGTCACCATCACTTGCCGGGCA AGTCAGAGCATAAGCAATTATGTAAATTGGTATCAGA AAAAAACAGGTCAAGTCCCTAAACTCCTGATCTATGG TGCATCCAATTTGGAAAGTGGGGTCCCATCAAGGTTC AGTGGCGGTGGATCTGGGACAGATTTCACTCTCACCA TCAGCAGTCTGCAACCTGAAGATTTTGCAACTTATTAC TGTCAACAGAGTTACAGTGTCCCGCTCACTTTCGGCG GAGGGACCAAGGTGGAAATCAAA 244 3898 202 DIVMTQSPSSLSASVGDRVTITCRASQSISNYVNWYQKK TGQVPKLLIYGASNLESGVPSRFSGGGSGTDFTLTISSLQP EDFATYYCQQSYSVPLTFGGGTKVEIK 244 3899 203 RASQSISNYVN 244 3900 204 CGGGCAAGTCAGAGCATAAGCAATTATGTAAAT 244 3901 205 GASNLES 244 3902 206 GGTGCATCCAATTTGGAAAGT 244 3903 207 QQSYSVPLT 244 3904 208 CAACAGAGTTACAGTGTCCCGCTCACT 245 3905 209 CAGGTCCAGCTTGTACAGTCTGGGGCTGAGGTGAAGA GGCCTGGATCCTCGGTGAAGGTCTCCTGCAAGGCGTC TGGAGGCACCTTCCGCGGCTACCATATCAGCTGGCTG CGCCAGGCCCCTGGACAGGGCCTCGAGTGGCTGGGAG GGATCACCCATTTGTTTGGGACAGTTAGTTACGCTCCG AAGTTCCAGGGCAGAGTCACCATCACCGCGGACGCAT CCACGGGCACACTTTACATGGTGTTGAACAGCCTGAA ACCTGAGGACACGGCCATTTATTATTGTGCGAGAGAT GCTTACGAGGTGTGGACTGGTTCTTATCTCCCCCCITT TGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCC TCA 245 3906 210 QVQLVQSGAEVKRPGSSVKVSCKASGGTFRGYHISWLR QAPGQGLEWLGGITHLFGTVSYAPKFQGRVTITADASTG TLYMVLNSLKPEDTAIYYCARDAYEVWTGSYLPPFDYW GQGTLVTVSS 245 3907 211 GTFRGYHIS 245 3908 212 GGCACCTTCCGCGGCTACCATATCAGC 245 3909 213 GITHLFGTVSYAPKFQG 245 3910 214 GGGATCACCCATTTGTTTGGGACAGTTAGTTACGCTCC GAAGTTCCAGGGC 245 3911 215 ARDAYEVWTGSYLPPFDY 245 3912 216 GCGAGAGATGCTTACGAGGTGTGGACTGGTTCTTATC TCCCCCCTTTTGACTAC 245 3913 217 GAAACGACACTCACGCAGTCTCCAGGCACCCTGTCTT TGTCTCCCGGGGAAAGAGCCACCCTCTCTTGCAGGGC CAGTCAGACTGTTACAAGCAACTACTTAGCCTGGTAC CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCT ATGATGCACTCACCAGGGCCACTGGCATCCCAGACAG GTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTC ACCATCAGCAGACTGGAGCCTGAAGATTTTGCACTTT ATTATTGTCAGCAGTATGGTAGTTCATTCCTCACTTTC GGCGGAGGGACCAAAGTGGATATCAAA 245 3914 218 ETTLTQSPGTLSLSPGERATLSCRASQTVTSNYLAWYQQ KPGQAPRLLIYDALTRATGIPDRFSGSGSGTDFTLTISRLE PEDFALYYCQQYGSSFLTFGGGTKVDIK 245 3915 219 RASQTVTSNYLA 245 3916 220 AGGGCCAGTCAGACTGTTACAAGCAACTACTTAGCC 245 3917 221 DALTRAT 245 3918 222 GATGCACTCACCAGGGCCACT 245 3919 223 QQYGSSFLT 245 3920 224 CAGCAGTATGGTAGTTCATTCCTCACT 246 3921 225 CAGGTGCAGCTGCAGGAGTCCGGGGCTGAGGTGAAG AAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTT CTGGAGGCGCCTTCAGCAGCTATGCTATCAGCTGGGT GCGACAGGCCCCTGGACAGGGCCTCGAGTGGCTGGGA GGGATCACCCATTTGTTTGGGACAGTTAGTTACGCTCC GAAGTTCCAGGGCAGAGTCACCATCACCGCGGACGCA TCCACGGGCACACTTTACATGGTGTTGAACAGCCTGA AACCTGAGGACACGGCCATTTATTATTGTGCGAGAGA TGCTTACGAGGTGTGGACTGGTTCTTATCTCCCCCCTT TTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTC CTCA 246 3922 226 QVQLQESGAEVKKPGSSVKVSCKASGGAFSSYAISWVR QAPGQGLEWLGGITHLFGTVSYAPKFQGRVTITADASTG TLYMVLNSLKPEDTAIYYCARDAYEVWTGSYLPPFDYW GQGTLVTVSS 246 3923 227 GAFSSYAIS 246 3924 228 GGCGCCTTCAGCAGCTATGCTATCAGC 246 3925 229 GITHLFGTVSYAPKFQG 246 3926 230 GGGATCACCCATTTGTTTGGGACAGTTAGTTACGCTCC GAAGTTCCAGGGC 246 3927 231 ARDAYEVWTGSYLPPFDY 246 3928 232 GCGAGAGATGCTTACGAGGTGTGGACTGGTTCTTATC TCCCCCCTTTTGACTAC 246 3929 233 GAAATTGTATTGACACAGTCTCCAGGCACCCTGTCTTT GTCTCCCGGGGAAAGAGCCACCCTCTCTTGCAGGGCC AGTCAGACTGTTACAAGCAACTACTTAGCCTGGTACC AGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTA TGATGCACTCACCAGGGCCACTGGCATCCCAGACAGG TTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCA CCATCAGCAGACTGGAGCCTGAAGATTTTGCACTTTA TTATTGTCAGCAGTATGGTAGTTCATTCCTCACTTTCG GCGGAGGGACCAAGCTGGAGATCAAA 246 3930 234 EIVLTQSPGTLSLSPGERATLSCRASQTVTSNYLAWYQQ KPGQAPRLLIYDALTRATGIPDRFSGSGSGTDFTLTISRLE PEDFALYYCQQYGSSFLTFGGGTKLEIK 246 3931 235 RASQTVTSNYLA 246 3932 236 AGGGCCAGTCAGACTGTTACAAGCAACTACTTAGCC 246 3933 237 DALTRAT 246 3934 238 GATGCACTCACCAGGGCCACT 246 3935 239 QQYGSSFLT 246 3936 240 CAGCAGTATGGTAGTTCATTCCTCACT 247 3937 241 CAGGTCCAGCTGGTACAGTCTGGAGCTGAGGTGAAGG AGCCTGGGGCCTCAGTGAGGGTCTCCTGCAAGGCTTC TGGTTACACCTTTACCAGCTATGGTATCAGCTGGGTGC GACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATG GATCAGCGCTTACAATGGTAACACAAACTATGCACAG AAGTTCCAGGGCAGAGTCACCGTGACCACAGACACAT CCACGAGCGCAGCCTACATGGAGCTGAGGAGCCTGAG ATCTGACGACACGGCCATTTATTACTGTGCGAGAGAT TCATTTTCACTGACTGGTGCTGGATTTCCTGACTACTG GGGCCAGGGAACCCTGGTCACCGTCTCCTCA 247 3938 242 QVQLVQSGAEVKEPGASVRVSCKASGYTFTSYGISWVR QAPGQGLEWMGWISAYNGNTNYAQKFQGRVTVTTDTS TSAAYMELRSLRSDDTAIYYCARDSFSLTGAGFPDYWG QGTLVTVSS 247 3939 243 YTFTSYGIS 247 3940 244 TACACCTTTACCAGCTATGGTATCAGC 247 3941 245 WISAYNGNTNYAQKFQG 247 3942 246 TGGATCAGCGCTTACAATGGTAACACAAACTATGCAC AGAAGTTCCAGGGC 247 3943 247 ARDSFSLTGAGFPDY 247 3944 248 GCGAGAGATTCATTTTCACTGACTGGTGCTGGATTTCC TGACTAC 247 3945 249 GAAATTGTAATGACGCAGTCTCCACTCTCCCTGCCCGT CACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTA GTCAAAGCCTCGTATACAGTGATGGAAACACCTACTT GAATTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGG CGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGT CCCAGACAGATTCAGCGGCAGTGGGTCAGACACTGAT TTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATG TTGGGGTTTATTACTGCATGCAAGCTACACAGTGGCCT CGCACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA 247 3946 250 EIVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGNTYLNW FQQRPGQSPRRLIYKVSNRDSGVPDRFSGSGSDTDFTLKI SRVEAEDVGVYYCMQATQWPRTFGQGTKVEIK 247 3947 251 RSSQSLVYSDGNTYLN 247 3948 252 AGGTCTAGTCAAAGCCTCGTATACAGTGATGGAAACA CCTACTTGAAT 247 3949 253 KVSNRDS 247 3950 254 AAGGTTTCTAACCGGGACTCT 247 3951 255 MQATQWPRT 247 3952 256 ATGCAAGCTACACAGTGGCCTCGCACG 248 3953 257 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCCTGGTCA AGCCTGGGGGGTCCCTGAGACTCTCCTGTGTAGCCTCT GGATTCACCTTCAGTAGCTATAACATCAACTGGGTCC GCCAGGCTCCAGGGAAGGGACTGGAGTGGGTCTCATC CATTAGTGGTGGTAGTAATTACATAGACTACGCAGAC TCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACG CCAAGAACTCACTGTATTTGCAAATGAACAACCTGCG AGCCGAAGACACGGCTGTGTATTACTGTGCGAGACTT GGCTATGGTGGTAACCCGGAGCTTGACTATTGGGGCC AGGGAACCCTGGTCACTGTCTCCTCA 248 3954 258 EVQLLESGGGLVKPGGSLRLSCVASGFTFSSYNINWVRQ APGKGLEWVSSISGGSNYIDYADSVKGRFTISRDNAKNS LYLQMNNLRAEDTAVYYCARLGYGGNPELDYWGQGTL VTVSS 248 3955 259 FTFSSYNIN 248 3956 260 TTCACCTTCAGTAGCTATAACATCAAC 248 3957 261 SISGGSNYIDYADSVKG 248 3958 262 TCCATTAGTGGTGGTAGTAATTACATAGACTACGCAG ACTCAGTGAAGGGC 248 3959 263 ARLGYGGNPELDY 248 3960 264 GCGAGACTTGGCTATGGTGGTAACCCGGAGCTTGACT AT 248 3961 265 CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGG CCCCAGGACAGAGGGTCACCATCTCCTGCACCGGGAG CAGCTCCAACATCGGGGCAGGTTATGATGTACACTGG TACCAGCAACGTCCAGGAACAGCCCCCAAACTCCTCA TCTATGCTAATAACAATCGGCCCTCAGGGGTCCCTGA CCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCC TGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGA TTATTACTGCCAGTCCTATGACCTCAGTCTGAGTAGTT CGAGGGTATTCGGCGGAGGGACCAAGCTGACCGTCCT C 248 3962 266 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QRPGTAPKLLIYANNNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDLSLSSSRVFGGGTKLTVL 248 3963 267 TGSSSNIGAGYDVH 248 3964 268 ACCGGGAGCAGCTCCAACATCGGGGCAGGTTATGATG TACAC 248 3965 269 ANNNRPS 248 3966 270 GCTAATAACAATCGGCCCTCA 248 3967 271 QSYDLSLSSSRV 248 3968 272 CAGTCCTATGACCTCAGTCTGAGTAGTTCGAGGGTA 249 3969 273 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCGTGGTCC AGCCTGGGAGGTCCCTGAAACACTCATGTGCAGCCTC TGGATTCACCTTCAATAACTATGCTATACACTGGGTCC GCCAGGCTCCAGGCAAGGGCCTGGAGTGGGTGGCAG CTATCTCATATGATGGAAGCAATGAATACTACTCAAA CTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAAT TCCAAGTACACGCTGTATCTGCAAATGAACAGCCTGA GACCTGAGGACACGGCTGTGTATTACTGTGCGAGAGG CGCCTCCTATTACTATGTGAGTAGTGACCTTGGCTACT GGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 249 3970 274 QVQLVQSGGGVVQPGRSLKHSCAASGFTFNNYAIHWVR QAPGKGLEWVAAISYDGSNEYYSNSVKGRFTISRDNSK YTLYLQMNSLRPEDTAVYYCARGASYYYVSSDLGYWG QGTLVTVSS 249 3971 275 FTFNNYAIH 249 3972 276 TTCACCTTCAATAACTATGCTATACAC 249 3973 277 AISYDGSNEYYSNSVKG 249 3974 278 GCTATCTCATATGATGGAAGCAATGAATACTACTCAA ACTCCGTGAAGGGC 249 3975 279 ARGASYYYVSSDLGY 249 3976 280 GCGAGAGGCGCCTCCTATTACTATGTGAGTAGTGACC TTGGCTAC 249 3977 281 CAGCCTGTGCTGACTCAGCCGCCCTCAGTGTCTGGGG CCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAG CAGCTCCAACATCGGGTCAGGTTATGATGTGCACTGG TATCAGCAGCTTCCAGGAACAGCCCCCAAAGTCGTCA TCTATGGTAACATCAATCGGCCCTCAGGGGTCCCTGA GCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCC TGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGA TTATTACTGCCAGTCCTATGACAGCCTGAGTGCCTCTT GGGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA 249 3978 282 QPVLTQPPSVSGAPGQRVTISCTGSSSNIGSGYDVHWYQ QLPGTAPKVVIYGNINRPSGVPERFSGSKSGTSASLAITG LQAEDEADYYCQSYDSLSASWVFGGGTKLTVL 249 3979 283 TGSSSNIGSGYDVH 249 3980 284 ACTGGGAGCAGCTCCAACATCGGGTCAGGTTATGATG TGCAC 249 3981 285 GNINRPS 249 3982 286 GGTAACATCAATCGGCCCTCA 249 3983 287 QSYDSLSASWV 249 3984 288 CAGTCCTATGACAGCCTGAGTGCCTCTTGGGTG 250 3985 289 CAGGTCCAGCTTGTGCAGTCTGGACCAGAGGTGAAAA AGACCAGAGAGTCTCTGAAGATCTACTGTAAGGGTTC TGGATACAGCTTTATCAGCCACTGGATCGGCTGGGTG CGCCAGAAACCCGGGAAAGGCCTGGAGTGGATGGGG ATCATCTATCCGGGTGACTCTGACACCAGATACAGCC CGTCCTTCCAAGGCCAGGTCGCCATCTCAGCCGACAA GTCCATCAACACCGCCTACCTGCAGTGGAGCAGCCTG AAGTCCTCGGACACCGCCATATATTACTGTGCGAGTG TAATGCTTCGGGGGATTATGTGGGGCCAGGGAACCCT GGTCACCGTCTCCTCA 250 3986 290 QVQLVQSGPEVKKTRESLKIYCKGSGYSFISHWIGWVRQ KPGKGLEWMGIIYPGDSDTRYSPSFQGQVAISADKSINT AYLQWSSLKSSDTAIYYCASVMLRGIMWGQGTLVTVSS 250 3987 291 YSFISHWIG 250 3988 292 TACAGCTTTATCAGCCACTGGATCGGC 250 3989 293 IIYPGDSDTRYSPSFQG 250 3990 294 ATCATCTATCCGGGTGACTCTGACACCAGATACAGCC CGTCCTTCCAAGGC 250 3991 295 ASVMLRGIM 250 3992 296 GCGAGTGTAATGCTTCGGGGGATTATG 250 3993 297 GACATCCGGTTGACCCAGTCTCCATCCTCCCTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCG AGTCAGGACATTAGCAAGTATCTAAATTGGTATCAGC AGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTACGA TGCATCCAATTTGGAAACAGGGGTCCCATCAAGATTC AGTGGAAGTGGATCTGGGACAGATTTTACTTTCACCA TCAGCAGCCTGCAGCCTGAAGATATTGCAACATATTA CTGTCAGCCGTATGATAATCTCCCTCCGCCGCTCACTT TCGGCGGAGGGACCAAGCTGGAGATCAAA 250 3994 298 DIRLTQSPSSLSASVGDRVTITCQASQDISKYLNWYQQKP GKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPE DIATYYCQPYDNLPPPLTFGGGTKLEIK 250 3995 299 QASQDISKYLN 250 3996 300 CAGGCGAGTCAGGACATTAGCAAGTATCTAAAT 250 3997 301 DASNLET 250 3998 302 GATGCATCCAATTTGGAAACA 250 3999 303 QPYDNLPPPLT 250 4000 304 CAGCCGTATGATAATCTCCCTCCGCCGCTCACT 251 4001 305 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCGTGGTCC AGTCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTC TGGATTCACCTTCAGTGACAATGGCATGCACTGGGTC CGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCA GGTATATTTTATGATGGAAGTAATAAACAATATGCAG ACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAA TTCCAAGAGCACGCTGTATCTGCAAATGAACAGCCTG AGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAG CCCCTTACGATATTTGGAGTGGTTATTGTCTTGACTAC TGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 251 4002 306 EVQLLESGGGVVQSGRSLRLSCAASGFTFSDNGMHWVR QAPGKGLEWVAGIFYDGSNKQYADSVKGRFTISRDNSK STLYLQMNSLRAEDTAVYYCARAPYDIWSGYCLDYWG QGTLVTVSS 251 4003 307 FTFSDNGMH 251 4004 308 TTCACCTTCAGTGACAATGGCATGCAC 251 4005 309 GIFYDGSNKQYADSVKG 251 4006 310 GGTATATTTTATGATGGAAGTAATAAACAATATGCAG ACTCCGTGAAGGGC 251 4007 311 ARAPYDIWSGYCLDY 251 4008 312 GCGAGAGCCCCTTACGATATTTGGAGTGGTTATTGTCT TGACTAC 251 4009 313 GACATCCAGATGACTCAGACTCCAGCCACCCTGTCTA TGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGC CAGTCAGAGTGTTAACAACAACTTAGCCTGGTACCAG CAGAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATG GTGCATCTACCAGGGCCACTGGTATCCCAGCCAGGTT CAGTGGCAGTGGGTCTGAGACAGAGTTCACTCTCACT ATCAGCAGCCTGCAGTCTGAAGATTTTGCGGTTTATCA CTGTCAGCAGTATAGTATCTGGCCTCAGACTTTTGGCC AGGGGACCAAGCTGGAGATCAAA 251 4010 314 DIQMTQTPATLSMSPGERATLSCRASQSVNNNLAWYQQ RPGQAPRLLIYGASTRATGIPARFSGSGSETEFTLTISSLQ SEDFAVYHCQQYSIWPQTFGQGTKLEIK 251 4011 315 RASQSVNNNLA 251 4012 316 AGGGCCAGTCAGAGTGTTAACAACAACTTAGCC 251 4013 317 GASTRAT 251 4014 318 GGTGCATCTACCAGGGCCACT 251 4015 319 QQYSIWPQT 251 4016 320 CAGCAGTATAGTATCTGGCCTCAGACT 252 4017 321 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCC AGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTC TGGATTCACTATTGGAACGTACTGGATGAGCTGGGTC CGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCC AACATAAAACCAGATGGAAGTGAGCAATATTATGGG GACTCGGTGAAGGGCCGATTCACCATCTCCAGAGACA ACGCCAAGAATTCCCTGTATCTGCAAATGCACAGCCT GAGAGCCGAGGACGCGGCTGTCTTTTACTGTGCGAGG GATACTCCCGACGTATTACGACATTTGGAGTGGCCCC CTGTAGGTGCTTTTGATATCTGGGGCCAAGGGACCAC GGTCACCGTCTCCTCA 252 4018 322 EVQLVESGGGLVQPGGSLRLSCAASGFTIGTYWMSWVR QAPGKGLEWVANIKPDGSEQYYGDSVKGRFTISRDNAK NSLYLQMHSLRAEDAAVFYCARDTPDVLRHLEWPPVG AFDIWGQGTTVTVSS 252 4019 323 FTIGTYWMS 252 4020 324 TTCACTATTGGAACGTACTGGATGAGC 252 4021 325 NIKPDGSEQYYGDSVKG 252 4022 326 AACATAAAACCAGATGGAAGTGAGCAATATTATGGG GACTCGGTGAAGGGC 252 4023 327 ARDTPDVLRHLEWPPVGAFDI 252 4024 328 GCGAGGGATACTCCCGACGTATTACGACATTTGGAGT GGCCCCCTGTAGGTGCTTTTGATATC 252 4025 329 GAAATTGTAATGACGCAGTCTCCAGACTCCCTGGCTG TGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTC CAGCCAGAGTCTTTTCTACAGCTCCACCAATCAGCACT ACTTGGCTTGGTACCAGCAGAAACCAGGACAGCCTCC TGAGCTGCTCATTTACTGGGCATCTATCCGGGAATCCG GGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGAC AGATTTCACTCTCACCATCAGCAGCCTGCAGGCCGCA GATGTGGCAGTTTATTACTGTCAGCAGTATTATAGTAG TCCTCAAACTTTTGGCCAGGGGACCAAGGTGGAAATC AAA 252 4026 330 EIVMTQSPDSLAVSLGERATINCKSSQSLFYSSTNQHYLA WYQQKPGQPPELLIYWASIRESGVPDRFSGSGSGTDFTL TISSLQAADVAVYYCQQYYSSPQTFGQGTKVEIK 252 4027 331 KSSQSLFYSSTNQHYLA 252 4028 332 AAGTCCAGCCAGAGTCTTTTCTACAGCTCCACCAATC AGCACTACTTGGCT 252 4029 333 WASIRES 252 4030 334 TGGGCATCTATCCGGGAATCC 252 4031 335 QQYYSSPQT 252 4032 336 CAGCAGTATTATAGTAGTCCTCAAACT 253 4033 337 CAGGTCCAGCTTGTGCAGTCTGGAACTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCTCCTGTAAGGCTGC TGGTTACACCTTTAGCAACTACGGTGTCAGTTGGGTGC GACAGGCCCCTGGACAGGGGCTTGAGTGGATGGGATG GATCAGCGCTTATAATGGTAACACAAAATTTGCACAG AAGGTCCAGGGCAGACTCACCATGACCACAGACACAT CTACCAGCACAGCCTACATGGAATTGAGGAACCTCAG ATCTGACGACACGGCCGTGTATTATTGTGCGAGAGAA TCAGGGGCAACAGCGGCTGCTATGTTTGACTACTGGG GCCAGGGAACCCTGGTCACCGTCTCCTCA 253 4034 338 QVQLVQSGTEVKKPGASVKVSCKAAGYTFSNYGVSWV RQAPGQGLEWMGWISAYNGNTKFAQKVQGRLTMTTDT STSTAYMELRNLRSDDTAVYYCARESGATAAAMFDYW GQGTLVTVSS 253 4035 339 YTFSNYGVS 253 4036 340 TACACCTTTAGCAACTACGGTGTCAGT 253 4037 341 WISAYNGNTKFAQKVQG 253 4038 342 TGGATCAGCGCTTATAATGGTAACACAAAATTTGCAC AGAAGGTCCAGGGC 253 4039 343 ARESGATAAAMFDY 253 4040 344 GCGAGAGAATCAGGGGCAACAGCGGCTGCTATGTTTG ACTAC 253 4041 345 GAAATTGTATTGACGCAGTCTCCACTCTCCCTGCCCGT CACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTA GTCAAAGCCTCGAATACAGTGATGGAAACATCTACTT GAGTTGGTTTCAACAGAGGCCAGGCCAATCTCCAAGG CGCCTAATTTATAAGGTTTCTCACCGGGACTCTGGGGT CCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGAT TTCACACTGAAAATCGCCAGGGTGGAGGCTGAGGATG TTGCAGTTTATTACTGCATGCAAGCTATACACTGGCCT CGAACTTTTGGCCAGGGGACCAAGGTGGAGATCAAA 253 4042 346 EIVLTQSPLSLPVTLGQPASISCRSSQSLEYSDGNIYLSWF QQRPGQSPRRLIYKVSHRDSGVPDRFSGSGSGTDFTLKIA RVEAEDVAVYYCMQAIHWPRTFGQGTKVEIK 253 4043 347 RSSQSLEYSDGNIYLS 253 4044 348 AGGTCTAGTCAAAGCCTCGAATACAGTGATGGAAACA TCTACTTGAGT 253 4045 349 KVSHRDS 253 4046 350 AAGGTTTCTCACCGGGACTCT 253 4047 351 MQAIHWPRT 253 4048 352 ATGCAAGCTATACACTGGCCTCGAACT 254 4049 353 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCC AGTCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTC TGGATTCACCTTCAGTGACAATGGCATGCACTGGGTC CGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCA GGTATATTTTATGATGGAAGTAATAAACAATATGCAG ACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAA TTCCAAGAGCACGCTGTATCTGCAAATGAACAGCCTG AGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAG CCCCTTACGATATTTGGAGTGGTTATTGTCTTGACTAC TGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 254 4050 354 EVQLVESGGGVVQSGRSLRLSCAASGFTFSDNGMHWVR QAPGKGLEWVAGIFYDGSNKQYADSVKGRFTISRDNSK STLYLQMNSLRAEDTAVYYCARAPYDIWSGYCLDYWG QGTLVTVSS 254 4051 355 FTFSDNGMH 254 4052 356 TTCACCTTCAGTGACAATGGCATGCAC 254 4053 357 GIFYDGSNKQYADSVKG 254 4054 358 GGTATATTTTATGATGGAAGTAATAAACAATATGCAG ACTCCGTGAAGGGC 254 4055 359 ARAPYDIWSGYCLDY 254 4056 360 GCGAGAGCCCCTTACGATATTTGGAGTGGTTATTGTCT TGACTAC 254 4057 361 GACATCCGGTTGACCCAGTCTCCAGCCACCCTGTCTAT GTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC AGTCAGAGTGTTAACAACAACTTAGCCTGGTACCAGC AGAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGG TGCATCTACCAGGGCCACTGGTATCCCAGCCAGGTTC AGTGGCAGTGGGTCTGAGACAGAGTTCACTCTCACTA TCAGCAGCCTGCAGTCTGAAGATTTTGCGGTTTATCAC TGTCAGCAGTATAGTATCTGGCCTCAGACTTTTGGCCA GGGGACCAAAGTGGATATCAAA 254 4058 362 DIRLTQSPATLSMSPGERATLSCRASQSVNNNLAWYQQR PGQAPRLLIYGASTRATGIPARFSGSGSETEFTLTISSLQSE DFAVYHCQQYSIWPQTFGQGTKVDIK 254 4059 363 RASQSVNNNLA 254 4060 364 AGGGCCAGTCAGAGTGTTAACAACAACTTAGCC 254 4061 365 GASTRAT 254 4062 366 GGTGCATCTACCAGGGCCACT 254 4063 367 QQYSIWPQT 254 4064 368 CAGCAGTATAGTATCTGGCCTCAGACT 255 4065 369 GAGGTGCAGCTGTTGGAGTCTGGGGGAGCCTTGGTCG AGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTC TGGATTCTCCTTTAACACGTATTCCATGAACTGGGTCC GCCAGGGTCCAGGGAAGGGACTGGAGTGGGTCGCAA CGATAAGTACGAGTACTGCTGGCTCATACTACGCAGA CTCCGTGAGGGGCCGGTTCACCATCTCTAGAGACAAT TCCAAGAACACGTTATATCTGCAAATGAACAGTCTGA GAGTCGAAGACACGGCCGTATATTACTGTGCGAGAGA TCAGGAAGTGGAACTGATCGATGATGCTTTTGATTTCT GGGGCCGGGGGACAATGGTCACCGTCTCTTCA 255 4066 370 EVQLLESGGALVEPGGSLRLSCAASGFSFNTYSMNWVR QGPGKGLEWVATISTSTAGSYYADSVRGRFTISRDNSKN TLYLQMNSLRVEDTAVYYCARDQEVELIDDAFDFWGR GTMVTVSS 255 4067 371 FSFNTYSMN 255 4068 372 TTCTCCTTTAACACGTATTCCATGAAC 255 4069 373 TISTSTAGSYYADSVRG 255 4070 374 ACGATAAGTACGAGTACTGCTGGCTCATACTACGCAG ACTCCGTGAGGGGC 255 4071 375 ARDQEVELIDDAFDF 255 4072 376 GCGAGAGATCAGGAAGTGGAACTGATCGATGATGCTT TTGATTTC 255 4073 377 GATATTGTGATGACTCAGACACATTCCTCCCTGTCTGC ATCTGTGGGAGACAGAGTCACCATCACTTGCCGGGCC AGTCAGAGTATTAGTATCTGGGTGGCCTGGTATCAGC AGAAACCAGGGAAAGCCCCTAACCTCCTGATCTATAA GGCGTCTAGTTTACAAAGTGGGGTCCCATCAAGGTTC AGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCA TCAGCAGCCTGCAGCCTGATGACTCTGCAACTTATTAC TGCCAACAGTATTACACCTATTACAGTTTTGGCCAGG GGACCAAGCTGGAGATCAAA 255 4074 378 DIVMTQTHSSLSASVGDRVTITCRASQSISIWVAWYQQK PGKAPNLLIYKASSLQSGVPSRFSGSGSGTEFTLTISSLQP DDSATYYCQQYYTYYSFGQGTKLEIK 255 4075 379 RASQSISIWVA 255 4076 380 CGGGCCAGTCAGAGTATTAGTATCTGGGTGGCC 255 4077 381 KASSLQS 255 4078 382 AAGGCGTCTAGTTTACAAAGT 255 4079 383 QQYYTYYS 255 4080 384 CAACAGTATTACACCTATTACAGT 256 4081 385 GAGGTGCAGCTGGTGGAGTCTGGGGCTGAGGTGAAG AGGCCTGGGGCCTCAGTGAAAATCTCCTGCAAGGCTT CTGAATACGCCTTCACCGCCCACTATCTTCACTGGGTG CGACAGGCCCCTGATCAAGGACTTGAGTGGATGGGAT GGATCAGCCCTAAAAGTGGTGGCACCAACTATGCACA GAAGTTTCACGGCAGGGTCAGCATGACCAGTGACACG TCCATCAGTACAGTCTATATGGAACTGAGCAGCCTGA CATCTGACGACACGGCCGTCTATTACTGTGCGAGAAG CAGTCTGGTGGGAGCAAGCCCCAACTTTGACTTCTGG GGCCAGGGAACCCTGGTCACCGTCTCCTCA 256 4082 386 EVQLVESGAEVKRPGASVKISCKASEYAFTAHYLHWVR QAPDQGLEWMGWISPKSGGTNYAQKFHGRVSMTSDTSI STVYMELSSLTSDDTAVYYCARSSLVGASPNFDFWGQG TLVTVSS 256 4083 387 YAFTAHYLH 256 4084 388 TACGCCTTCACCGCCCACTATCTTCAC 256 4085 389 WISPKSGGTNYAQKFHG 256 4086 390 TGGATCAGCCCTAAAAGTGGTGGCACCAACTATGCAC AGAAGTTTCACGGC 256 4087 391 ARSSLVGASPNFDF 256 4088 392 GCGAGAAGCAGTCTGGTGGGAGCAAGCCCCAACTTTG ACTTC 256 4089 393 CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGCGG CCCCAGGACAGAGGGTCACCATCTCCTGCTCTGGAAG CAGCTCCAACATTGGGAATAATTATGTATCCTGGTAC CAGCAACTCCCAGGAACTACCCCCAAAGTCCTCATTT ACGACAATAATCAGCGACCCTCAGGGATTCCTGACCG TTTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGG CCATCAGCGGACTCCAGACTGGCGACGAGGCCGTCTA TTATTGCGGAACATGGGATGCCAGCCTGAGTGCTGCT ATGGTTTTCGGCGGGGGGACCAAGCTCACCGTCCTA 256 4090 394 QSVLTQPPSVSAAPGQRVTISCSGSSSNIGNNYVSWYQQ LPGTTPKVLIYDNNQRPSGIPDRFSGSKSGTSATLAISGLQ TGDEAVYYCGTWDASLSAAMVFGGGTKLTVL 256 4091 395 SGSSSNIGNNYVS 256 4092 396 TCTGGAAGCAGCTCCAACATTGGGAATAATTATGTAT CC 256 4093 397 DNNQRPS 256 4094 398 GACAATAATCAGCGACCCTCA 256 4095 399 GTWDASLSAAMV 256 4096 400 GGAACATGGGATGCCAGCCTGAGTGCTGCTATGGTT 257 4097 401 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGA AGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCT GGTGGCTCCATCAGCGGATATTACTGGAGCTGGATCC GGCAGCCCCCAGGGAGGGGACTGGAGTGGATTGGGTT TATTTATTATAGTGGGAGTACCAGCTACGACTCCTCCC TCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAA GAACCAGTTCTCCCTAAACCTGAGCTCTGTGACCGCT GCGGACACGGCCGTATATTACTGTGCGAGAAGTACAT GGGACTACGGTGACCACTTTCCGTTTGACTACTGGGG CCAGGGAACCCTGGTCACCGTCTCCTCA 257 4098 402 QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQ PPGRGLEWIGFIYYSGSTSYDSSLKSRVTISVDTSKNQFSL NLSSVTAADTAVYYCARSTWDYGDHFPFDYWGQGTLV TVSS 257 4099 403 GSISGYYWS 257 4100 404 GGCTCCATCAGCGGATATTACTGGAGC 257 4101 405 FIYYSGSTSYDSSLKS 257 4102 406 TTTATTTATTATAGTGGGAGTACCAGCTACGACTCCTC CCTCAAGAGT 257 4103 407 ARSTWDYGDHFPFDY 257 4104 408 GCGAGAAGTACATGGGACTACGGTGACCACTTTCCGT TTGACTAC 257 4105 409 TCCTATGAGCTGACTCAGCCACCCTCAGTGTCAGTGG CCCCAGGAAAGACGGCCAGGATTACCTGTGGGGGAA ACAACATTGGAATTAAAGATGTGCACTGGTACCAACT GAGGCCAGGCCAGGCCCCTGTGTTGGTCATCTCTTAT GATAGCGACCGGCCCTCAGGGATCCCTGAGCGATTCT CTGGCTCCAACTCTGGGAACACGGCCACCCTGACCAT CAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTTC TGTCAGGTGTGGGATAGTAGTCCTGATCATCCTTATGT CTTCGGAACTGGGACCAAGCTCACCGTCCTA 257 4106 410 SYELTQPPSVSVAPGKTARITCGGNNIGIKDVHWYQLRP GQAPVLVISYDSDRPSGIPERFSGSNSGNTATLTISRVEAG DEADYFCQVWDSSPDHPYVFGTGTKLTVL 257 4107 411 GGNNIGIKDVH 257 4108 412 GGGGGAAACAACATTGGAATTAAAGATGTGCAC 257 4109 413 YDSDRPS 257 4110 414 TATGATAGCGACCGGCCCTCA 257 4111 415 QVWDSSPDHPYV 257 4112 416 CAGGTGTGGGATAGTAGTCCTGATCATCCTTATGTC 258 4113 417 GAGGTGCAGCTGGTGGAGTCTGGAGGTGAGGTGAAG AAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAGGGCCT CTGGTTACACCTTTAGAAACTATGGCCTCACCTGGGTG CGGCAGGCCCCCGGACAAGGGCTTGAGTGGATGGGAT GGATCAGCGCTTACAATGGAAACACAAACTATGCACA GAAGTTCCAGGGCAGAGTCACACTGACCACGGACACA TCCACGAGCACAGCCTACATGGAACTGAGGAGCCTAA GATCTGACGACACGGCCGTGTATTTCTGTGCGAGAGA CGTCCCCGGCCACGGCGCTGCCTTCATGGACGTCTGG GGCACAGGGACCACGGTCACCGTCTCCTCA 258 4114 418 EVQLVESGGEVKKPGASVKVSCRASGYTFRNYGLTWVR QAPGQGLEWMGWISAYNGNTNYAQKFQGRVTLTTDTS TSTAYMELRSLRSDDTAVYFCARDVPGHGAAFMDVWG TGTTVTVSS 258 4115 419 YTFRNYGLT 258 4116 420 TACACCTTTAGAAACTATGGCCTCACC 258 4117 421 WISAYNGNTNYAQKFQG 258 4118 422 TGGATCAGCGCTTACAATGGAAACACAAACTATGCAC AGAAGTTCCAGGGC 258 4119 423 ARDVPGHGAAFMDV 258 4120 424 GCGAGAGACGTCCCCGGCCACGGCGCTGCCTTCATGG ACGTC 258 4121 425 GAAACGACACTCACGCAGTCTCCACTCTCCCTGCCCG TCACCCTTGGGCAGCCGGCCTCCATCTCCTGCAGGTCT AGTCAAAGCCTCGAAGCCAGTGATACAAATATCTACT TGAGTTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAG GCGCCTAATTTATAAGATTTCTAACCGAGACTCTGGG GTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTC ATTTCACACTGAGAATCAGCAGGGTGGAGGCTGACGA TGTTGCGGTTTATTACTGCATGCAGGGTACACACTGGC CTCCGGCGTTCGGCCAGGGGACCAAGCTGGAGATCAA A 258 4122 426 ETTLTQSPLSLPVTLGQPASISCRSSQSLEASDTNIYLSWF QQRPGQSPRRLIYKISNRDSGVPDRFSGSGSGTHFTLRISR VEADDVAVYYCMQGTHWPPAFGQGTKLEIK 258 4123 427 RSSQSLEASDTNIYLS 258 4124 428 AGGTCTAGTCAAAGCCTCGAAGCCAGTGATACAAATA TCTACTTGAGT 258 4125 429 KISNRDS 258 4126 430 AAGATTTCTAACCGAGACTCT 258 4127 431 MQGTHWPPA 258 4128 432 ATGCAGGGTACACACTGGCCTCCGGCG 259 4129 433 GAGGTGCAGCTGGTGGAGTCTGGATCTGAGGTGAAGA AGCCTGGGGCCGCAGTGAAGGTATCCTGCAAGGCTTC TGGTTACATCTTTGCCAACTTTGGTGTCAGCTGGGTGC GACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATG GATCAGCGCTTACAATGGTAACACAAACTATGCACAG AAGTTCCAGGGCAGAGTCATCATGACCACAGACACAT CCACGAGCACAGCCTACATGGAGCTGAGGAGCCTGAG ATCTGACGACACGGCCGTGTATTATTGTGCGAGAGAC CCCCCCGCCTACGCCGCTACATTGATGGACGTCTGGG GCAAAGGGACCACGGTCACCGTCTCCTCA 259 4130 434 EVQLVESGSEVKKPGAAVKVSCKASGYIFANFGVSWVR QAPGQGLEWMGWISAYNGNTNYAQKFQGRVIMTTDTS TSTAYMELRSLRSDDTAVYYCARDPPAYAATLMDVWG KGTTVTVSS 259 4131 435 YIFANFGVS 259 4132 436 TACATCTTTGCCAACTTTGGTGTCAGC 259 4133 437 WISAYNGNTNYAQKFQG 259 4134 438 TGGATCAGCGCTTACAATGGTAACACAAACTATGCAC AGAAGTTCCAGGGC 259 4135 439 ARDPPAYAATLMDV 259 4136 440 GCGAGAGACCCCCCCGCCTACGCCGCTACATTGATGG ACGTC 259 4137 441 GATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGT CACCCTTGGACAGTCGGCCTCCATCTCCTGCAGGTCTA GTCAAAGCCTCGAACACAGTGATACAAACACCTACTT GACTTGGTATCAGCAGAGGCCAGGCCAATCTCCAAGG CGGCTACTTTATAAGGTTTCTAACCGGGACTCTGGGGT CCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGAT TTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATG TTGGGGTTTATTACTGCATGCAAGGTACACACTGGCCT CCGACGTTCGGCCAAGGGACCAAGCTGGAGATCAAA 259 4138 442 DIVMTQSPLSLPVTLGQSASISCRSSQSLEHSDTNTYLTW YQQRPGQSPRRLLYKVSNRDSGVPDRFSGSGSGTDFTLK ISRVEAEDVGVYYCMQGTHWPPTFGQGTKLEIK 259 4139 443 RSSQSLEHSDTNTYLT 259 4140 444 AGGTCTAGTCAAAGCCTCGAACACAGTGATACAAACA CCTACTTGACT 259 4141 445 KVSNRDS 259 4142 446 AAGGTTTCTAACCGGGACTCT 259 4143 447 MQGTHWPPT 259 4144 448 ATGCAAGGTACACACTGGCCTCCGACG 260 4145 449 GAGGTGCAGCTGGTGGAGTCTGGCCCAACACTGGTGA AGCCTTCGGAGACCCTGTCCCTCACCTGCGTTGTCTCT GGTGGCTCCGTCTACAGGAGTAGTAACTACTGGGCCT GGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGA TCGGGAGTGTCTATCATAGTGGGAACCCCTACTCCAA CCCGTCCCTTCAGAGTCGAGTCTCCGTCTCCATTGACA CGTCCAAGAACCAGTTCTCCCTGAAGCTGTACTCTGTG ACCGCCGCAGACTCGGCTATTTATTATTGTGCGTGTAA AAGAGCGGACGCTGACGACGTAGATTACGTGGCGGG CCTCACCGGTTTCCCCTGGTACTTCGATGTCTGGGGCC GTGGCACCCTGGTCACCGTCTCCTCA 260 4146 450 EVQLVESGPTLVKPSETLSLTCVVSGGSVYRSSNYWAWI RQPPGKGLEWIGSVYHSGNPYSNPSLQSRVSVSIDTSKN QFSLKLYSVTAADSAIYYCACKRADADDVDYVAGLTGF PWYFDVWGRGTLVTVSS 260 4147 451 GSVYRSSNYWA 260 4148 452 GGCTCCGTCTACAGGAGTAGTAACTACTGGGCC 260 4149 453 SVYHSGNPYSNPSLQS 260 4150 454 AGTGTCTATCATAGTGGGAACCCCTACTCCAACCCGT CCCTTCAGAGT 260 4151 455 ACKRADADDVDYVAGLTGFPWYFDV 260 4152 456 GCGTGTAAAAGAGCGGACGCTGACGACGTAGATTACG TGGCGGGCCTCACCGGTTTCCCCTGGTACTTCGATGTC 260 4153 457 GAAATTGTGTTGACGCAGTCTCCGTCCACCCTGTCTGC ATCTGTGGGAGACAGAGTCACCATCACTTGCCGGGCC AGTCAGAGTATTAGTAGTTGGTTGGCCTGGTATCAGC AGAAACCAGGGAAAACCCCTAAGTTGCTCATCTATAA GGCGTCTACTTTAGAAAGTGGGGTCCCATCAAGGTTC AGCGGCAGCGGATCTGGGACAGAATTCACTCTCACCA TCAGCAGCCTGCAGCCTGATGATTTCGCAACCTACTA CTGCCAACAGTATCATGTTTATTTCCCGCTCACTTTCG GCGGAGGGACCAAGGTGGAAATCAAA 260 4154 458 EIVLTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKP GKTPKLLIYKASTLESGVPSRFSGSGSGTEFTLTISSLQPD DFATYYCQQYHVYFPLTFGGGTKVEIK 260 4155 459 RASQSISSWLA 260 4156 460 CGGGCCAGTCAGAGTATTAGTAGTTGGTTGGCC 260 4157 461 KASTLES 260 4158 462 AAGGCGTCTACTTTAGAAAGT 260 4159 463 QQYHVYFPLT 260 4160 464 CAACAGTATCATGTTTATTTCCCGCTCACT 261 4161 465 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCC AGCCTGGGAGGTCCCTGAGACTCTCCTGTGTAGCGTC TGGATTCAGCTTCAGTATGCATGGCATGCACTGGGTC CGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGACA GCTATATGGTATGATGGAAGTAATAAATATTATGCAG ACTCCGTGAAGGGCCGATTCACGATCTCCAGAGACAA TTCTAGGAACACGCTGTATCTGCAAATGAACAGCCTG AGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAG ATCATGCCTCAACTCCATACTACATGGACGTCTGGGG CAAAGGGACCACGGTCACCGTCTCTTCA 261 4162 466 EVQLVESGGGVVQPGRSLRLSCVASGFSFSMHGMHWV RQAPGKGLEWVTAIWYDGSNKYYADSVKGRFTISRDNS RNTLYLQMNSLRAEDTAVYYCARDHASTPYYMDVWG KGTTVTVSS 261 4163 467 FSFSMHGMH 261 4164 468 TTCAGCTTCAGTATGCATGGCATGCAC 261 4165 469 AIWYDGSNKYYADSVKG 261 4166 470 GCTATATGGTATGATGGAAGTAATAAATATTATGCAG ACTCCGTGAAGGGC 261 4167 471 ARDHASTPYYMDV 261 4168 472 GCGAGAGATCATGCCTCAACTCCATACTACATGGACG TC 261 4169 473 GAAACGACACTCACGCAGTCTCCAGGCACCCTGTCTT TGTCTCCAGGGGAAAGCGCCACCCTCTCCTGCAGGAC CAGTCAGAGGATTAGCAGCACCTACTTAGCCTGGTAC CGGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATGT ATGGTGCATCCAGCAGGGCCACTGGCATCCCGGACAG GTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTC ACCATCAGCAGTCTGGAGCCTGAAGATTTTGCACTAT ATTACTGTCAGCAGTATGGTAGCTTTCCGTGGACGTTC GGCCAAGGGACCAAGGTGGAAATCAAA 261 4170 474 ETTLTQSPGTLSLSPGESATLSCRTSQRISSTYLAWYRQK PGQAPRLLMYGASSRATGIPDRFSGSGSGTDFTLTISSLEP EDFALYYCQQYGSFPWTFGQGTKVEIK 261 4171 475 RTSQRISSTYLA 261 4172 476 AGGACCAGTCAGAGGATTAGCAGCACCTACTTAGCC 261 4173 477 GASSRAT 261 4174 478 GGTGCATCCAGCAGGGCCACT 261 4175 479 QQYGSFPWT 261 4176 480 CAGCAGTATGGTAGCTTTCCGTGGACG 262 4177 481 CAGGTCCAGCTGGTGCAGTCTGGGCCTGAGGTGAAGA AGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTC TGGAGGCACCTTCAGCAGTTATGCTATCACGTGGGTG CGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGG GGGATCATCCCTTCCTTTGATAGAGTGGACTATTCACG GAACTTCAAGGGGAGAGTCACCTTTACCGCGGACAAA TCCGCGAACACGGCCTACATGGAACTGACCAATGTGA GATCCGACGACACGGCCGTGTATTACTGTGCGAGAGG CTGTTGTGGGGCTGTGGCTGGATTCCAGCACTGGGGC CAGGGCACCGGGGTCACCGTCTCCTCA 262 4178 482 QVQLVQSGPEVKKPGSSVKVSCKASGGTFSSYAITWVR QAPGQGLEWMGGIIPSFDRVDYSRNFKGRVTFTADKSA NTAYMELTNVRSDDTAVYYCARGCCGAVAGFQHWGQ GTGVTVSS 262 4179 483 GTFSSYAIT 262 4180 484 GGCACCTTCAGCAGTTATGCTATCACG 262 4181 485 GIIPSFDRVDYSRNFKG 262 4182 486 GGGATCATCCCTTCCTTTGATAGAGTGGACTATTCACG GAACTTCAAGGGG 262 4183 487 ARGCCGAVAGFQH 262 4184 488 GCGAGAGGCTGTTGTGGGGCTGTGGCTGGATTCCAGC AC 262 4185 489 GATATTGTGCTGACGCAGACTCCAGCCACCCTGTCTTT ATCTCCAGGGGAAACAGCCACCCTCTCCTGCAGGGCC AGTCAGAGTGTTACCACCTACTTAGCCTGGTACCAGC AGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGA TGCATCCAACAGGGCCACTGGCGTCCCAACCAGGTTC AGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCA TCAGCAGCCTGGAGCCTGAAGATTATGCGATTTATTA CTGTCAGCAACGTACTACCGGGGTCACTTTCGGCGGG GGGACCAAGGTGGAAATCAAA 262 4186 490 DIVLTQTPATLSLSPGETATLSCRASQSVTTYLAWYQQK PGQAPRLLIYDASNRATGVPTRFSGSGSGTDFTLTISSLEP EDYAIYYCQQRTTGVTFGGGTKVEIK 262 4187 491 RASQSVTTYLA 262 4188 492 AGGGCCAGTCAGAGTGTTACCACCTACTTAGCC 262 4189 493 DASNRAT 262 4190 494 GATGCATCCAACAGGGCCACT 262 4191 495 QQRTTGVT 262 4192 496 CAGCAACGTACTACCGGGGTCACT 263 4193 497 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCA AGCCTGGGGGGTCCCTGAGACTCTCTTGTGCAGCCTCT GGATTCACCTTCAGTAGTTTTGGCATGCATTGGGTCCG CCAGGCTCCAGGGCAGGGACTGGAGTGGGTCGCATCC ATTACTGGTGGCAGCAGTTACATAAACTACGCAGACT CAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGC CAAGAAGTCACTGTCTCTGCAAATGAAGAACCTGAGA GCCGAGGACACGGCTGAGTATTACTGTGTGCGAGGAG TCCTACCAGGTGGTACTGGGGGGGGCTGGTTCGACTC CTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 263 4194 498 QVQLVESGGGLVKPGGSLRLSCAASGFTFSSFGMHWVR QAPGQGLEWVASITGGSSYINYADSVKGRFTISRDNAKK SLSLQMKNLRAEDTAEYYCVRGVLPGGTGGGWFDSWG QGTLVTVSS 263 4195 499 FTFSSFGMH 263 4196 500 TTCACCTTCAGTAGTTTTGGCATGCAT 263 4197 501 SITGGSSYINYADSVKG 263 4198 502 TCCATTACTGGTGGCAGCAGTTACATAAACTACGCAG ACTCAGTGAAGGGC 263 4199 503 VRGVLPGGTGGGWFDS 263 4200 504 GTGCGAGGAGTCCTACCAGGTGGTACTGGGGGGGGCT GGTTCGACTCC 263 4201 505 CAGTCTGTCCTGACTCAGCCGCCCTCAATGTCTGGGGC CCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGACC AGCTCCAACATCGGGGCGGGTTATGATGTACAGTGGT ATCAGCAGTTTCCAGGAACAGCCCCCAAACTCCTCAT CTCTGGTAACAACAATCGGCCCTCAGGGGTCCCTGAC CGATTCTCTGGCTCCAAGTCTGGCGCCTCAGCCTCCCT GGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGAT TATTACTGCCAGTCCTATGACTACAGCCTGAATTGGGT GTTCGGCGGAGGGACCAAGCTCACCGTCCTA 263 4202 506 QSVLTQPPSMSGAPGQRVTISCTGTSSNIGAGYDVQWYQ QFPGTAPKLLISGNNNRPSGVPDRFSGSKSGASASLAITG LQAEDEADYYCQSYDYSLNWVFGGGTKLTVL 263 4203 507 TGTSSNIGAGYDVQ 263 4204 508 ACTGGGACCAGCTCCAACATCGGGGCGGGTTATGATG TACAG 263 4205 509 GNNNRPS 263 4206 510 GGTAACAACAATCGGCCCTCA 263 4207 511 QSYDYSLNWV 263 4208 512 CAGTCCTATGACTACAGCCTGAATTGGGTG 264 4209 513 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGA AGCCTTCACAGACCCTGTCGCTCACCTGCACTGTCTCT GGTCGCTTCCTCAATAGTGGTGATTACTACTGGAGTTG GATCCGCCAGTCCCCAGGGAAGGGCCTGGAGTGGCTT GGTTACATCCATCACAGTGGGAACACCTACTACAACC CGTCCCTCAAGAGTCGACTTACCATATCACTAGACAT GTCCAAGAACCAGTTCTCCCTGAAGTTGAGCTCTGTG ACAGCCGCAGACACGGCCGTCTATTACTGTGCCAGAG ATTTGGGAAAGCCGCTTTGGGACGGCCACTATTACTA CGGAGTGGACGTCTGGGGCCAAGGGACCACGGTCACC GTCTCCTCA 264 4210 514 QVQLQESGPGLVKPSQTLSLTCTVSGRFLNSGDYYWSWI RQSPGKGLEWLGYIHHSGNTYYNPSLKSRLTISLDMSKN QFSLKLSSVTAADTAVYYCARDLGKPLWDGHYYYGVD VWGQGTTVTVSS 264 4211 515 RFLNSGDYYWS 264 4212 516 CGCTTCCTCAATAGTGGTGATTACTACTGGAGT 264 4213 517 YIHHSGNTYYNPSLKS 264 4214 518 TACATCCATCACAGTGGGAACACCTACTACAACCCGT CCCTCAAGAGT 264 4215 519 ARDLGKPLWDGHYYYGVDV 264 4216 520 GCCAGAGATTTGGGAAAGCCGCTTTGGGACGGCCACT ATTACTACGGAGTGGACGTC 264 4217 521 GATATTGTGATGACTCAGTCTCCAGGCACTCTGTCTTT GTCTCCAGGAGAAAGAGCCACCCTCTCCTGCAGGACC AGTCAGAATGTTAACAGCAACTACTTAGCCTGGTACC AGCATAAACCTGGGCAGGCTCCCAGGCTCCTCATCTA TGGTGCATCCAGCAGGGTCACTGGCATCCCAGACAGG TTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCA CCATCACCAGAGTGGAGTCTGAAGATTTTGCAGTGTA TTACTGTCAGGTGTATAGTAGTTCACCTCCGATCACCT TCGGCCAGGGGACCAAGGTGGAGATCAAA 264 4218 522 DIVMTQSPGTLSLSPGERATLSCRTSQNVNSNYLAWYQH KPGQAPRLLIYGASSRVTGIPDRFSGSGSGTDFTLTITRVE SEDFAVYYCQVYSSSPPITFGQGTKVEIK 264 4219 523 RTSQNVNSNYLA 264 4220 524 AGGACCAGTCAGAATGTTAACAGCAACTACTTAGCC 264 4221 525 GASSRVT 264 4222 526 GGTGCATCCAGCAGGGTCACT 264 4223 527 QVYSSSPPIT 264 4224 528 CAGGTGTATAGTAGTTCACCTCCGATCACC 265 4225 529 CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGA AGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTC TGGAGGCACCTTCAGCAGTTATGCTATCAGCTGGGTG CGTCAGGCCCCAGGACAAGGGCTTGAGTGGATGGGA GGAATCATCCCTATGTTTGATATAGTCGACTACGCAC AGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGA ATCCACGAACACAGCCTACATGGAGCTGACCAGCCTG AGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAA CTGCGGCTTTAGGACCACCTGGGACTATAGTGGGGTA CATGGACGTCTGGGGCAAAGGGACCACGGTCACCGTC TCCTCA 265 4226 530 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVR QAPGQGLEWMGGIIPMFDIVDYAQKFQGRVTITADESTN TAYMELTSLRSEDTAVYYCARTAALGPPGTIVGYMDVW GKGTTVTVSS 265 4227 531 GTFSSYAIS 265 4228 532 GGCACCTTCAGCAGTTATGCTATCAGC 265 4229 533 GIIPMFDIVDYAQKFQG 265 4230 534 GGAATCATCCCTATGTTTGATATAGTCGACTACGCAC AGAAGTTCCAGGGC 265 4231 535 ARTAALGPPGTIVGYMDV 265 4232 536 GCGAGAACTGCGGCTTTAGGACCACCTGGGACTATAG TGGGGTACATGGACGTC 265 4233 537 GATATTGTGATGACGCAGTCTCCACTCTCCCTGCCCGT CACCCCTGGAGAGCCGGCCTCCATCTCCTGCCGGTCT AGTCAGAGCCTCCTGCAAAGTAATGGATACAACTATT TGGATTGGTACCTGCAGAAGCCAGGGCAGGCTCCACA GCTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGG TCCCTGACAAGTTCAGTGGCAGTGGATCAGGCACAGA TTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGGAT GTTGGGGTTTATTACTGCATGCAAACTCTACAAACTCC GTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAA A 265 4234 538 DIVMTQSPLSLPVTPGEPASISCRSSQSLLQSNGYNYLDW YLQKPGQAPQLLIYLGSNRASGVPDKFSGSGSGTDFTLKI SRVEAEDVGVYYCMQTLQTPWTFGQGTKVEIK 265 4235 539 RSSQSLLQSNGYNYLD 265 4236 540 CGGTCTAGTCAGAGCCTCCTGCAAAGTAATGGATACA ACTATTTGGAT 265 4237 541 LGSNRAS 265 4238 542 TTGGGTTCTAATCGGGCCTCC 265 4239 543 MQTLQTPWT 265 4240 544 ATGCAAACTCTACAAACTCCGTGGACG 266 4241 545 CAGGTGCAGCTGGTGGAGTCTGGAGCAGAGGCGAGA AAGCCCGGGGAGTCTCTGAAGATCTCCTGTAAGGCTT CTGGATACAGCTTTACCAATTATTGGATCGGCTGGGT GCGCCAGATGCCCGGGAAAGGCCTGGAGTGGATGGG GGTCATCTATCCTGCTGACTCCGATACCAGATATAGCC CGTCCTTCAAAGGCCAGGTCACCATCTCAGCCGACAA ATCCATCAGCACCGCCTACCTCCAGTGGACCAGACTG AAGGCCTCGGACACCGCCGTGTATTTCTGTGCGAGAC TTGGAATAGGAGCTGCTGCCCGGAACTACTGGGGCCA GGGAACCCTGGTCACCGTCTCTTCA 266 4242 546 QVQLVESGAEARKPGESLKISCKASGYSFTNYWIGWVR QMPGKGLEWMGVIYPADSDTRYSPSFKGQVTISADKSIS TAYLQWTRLKASDTAVYFCARLGIGAAARNYWGQGTL VTVSS 266 4243 547 YSFTNYWIG 266 4244 548 TACAGCTTTACCAATTATTGGATCGGC 266 4245 549 VIYPADSDTRYSPSFKG 266 4246 550 GTCATCTATCCTGCTGACTCCGATACCAGATATAGCCC GTCCTTCAAAGGC 266 4247 551 ARLGIGAAARNY 266 4248 552 GCGAGACTTGGAATAGGAGCTGCTGCCCGGAACTAC 266 4249 553 GACATCCAGGTGACCCAGTCTCCATCCTCCCTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCG AGTCAGGACATTAGCGACAGTTTAAATTGGTATCAGC AGAAACCAGGGAAAGCCCCTAACCTCCTGATCTACGA TGCATCCAAGTCGGAAACAGGGGTCCCATCAAGATTC AGTGGAAGCGGATCTGGGACAGATTTCACTTTCACCA TCAGTAGCCTGCAGCCTGAAGATCTTGCAACATATTA CTGTCTACAGTTTGATAATCTCCCTCCGACCTTCGGCC AAGGGACACGACTGGAGATTAAA 266 4250 554 DIQVTQSPSSLSASVGDRVTITCQASQDISDSLNWYQQKP GKAPNLLIYDASKSETGVPSRFSGSGSGTDFTFTISSLQPE DLATYYCLQFDNLPPTFGQGTRLEIK 266 4251 555 QASQDISDSLN 266 4252 556 CAGGCGAGTCAGGACATTAGCGACAGTTTAAAT 266 4253 557 DASKSET 266 4254 558 GATGCATCCAAGTCGGAAACA 266 4255 559 LQFDNLPPT 266 4256 560 CTACAGTTTGATAATCTCCCTCCGACC 267 4257 561 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCA AGCCTGGGGGGGCCCTGAGACTCTCCTGTGCAGCCTC TGGATTCAGCTTCAGGAGCTATAGCATGAACTGGGTC CGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTAGTAGTAGTAGTAATTACATAAACTACGCAGA CTCAGTGAAGGGCCGATTCAGCATCTCCAGAGACAAC GCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGA GAGCCGAGGACACGGCTGTCTATTACTGTGCGAGAGA TTTGTTACCCGTCGAGCGGGGTCCCGCTTTTGATATCT GGGGCCAAGGGACAATGGTCACCGTCTCTTCA 267 4258 562 EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVR QAPGKGLEWVSSISSSSNYINYADSVKGRFSISRDNAKNS LYLQMNSLRAEDTAVYYCARDLLPVERGPAFDIWGQGT MVTVSS 267 4259 563 FSFRSYSMN 267 4260 564 TTCAGCTTCAGGAGCTATAGCATGAAC 267 4261 565 SISSSSNYINYADSVKG 267 4262 566 TCCATTAGTAGTAGTAGTAATTACATAAACTACGCAG ACTCAGTGAAGGGC 267 4263 567 ARDLLPVERGPAFDI 267 4264 568 GCGAGAGATTTGTTACCCGTCGAGCGGGGTCCCGCTT TTGATATC 267 4265 569 TCCTATGAGCTGACACAGCCACCCTCAGTGTCTGGGG CCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAG CAGCTCCAACATCGGGGCAGGTTATGATGTACACTGG TTCCAGCAGCTTCCAGGAGCAGCCCCCAAACTCCTCA TCTATGCTAACAGCAATCGGCCCTCAGGGGTCCCTGA CCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCC TGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGA TTATTACTGCCAGTCCTATGACAGCAGACTGGGTGGTT CGGTATTCGGCGGAGGGACCAAGGTGACCGTCCTA 267 4266 570 SYELTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWFQ QLPGAAPKLLIYANSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSRLGGSVFGGGTKVTVL 267 4267 571 TGSSSNIGAGYDVH 267 4268 572 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATG TACAC 267 4269 573 ANSNRPS 267 4270 574 GCTAACAGCAATCGGCCCTCA 267 4271 575 QSYDSRLGGSV 267 4272 576 CAGTCCTATGACAGCAGACTGGGTGGTTCGGTA 268 4273 577 CAGGTCCAGCTTGTGCAGTCTGGACCAGAGGTGAAAA AGCCCGGGGAGTCTCTGACGATCTCCTGTAAGGGTTC TGGATACGACTTTTCCAATAACTGGATCGGCTGGGTG CGCCAGATGCCCGGGAAAGGCCTGGAGTGGATGGGA ATCATCTATCCTGGTGACTCTGATACCAGATACAGCCC GTCGTTCCAAGGCCAGGTCACCCTCTCAGTCGACAAG TCCATTAGTACCGCCTACCTACAGTGGAGGAGCCTGA AGGCCTCGGACAGCGGCATCTACTACTGTGCGAGACA AATTGGCGGTTTGGTTTGTAGCAGTGAGAGCTGCTAC TTCTACGGCATGGACGTCTGGGGCCAAGGGACCACGG TCACCGTCTCCTCA 268 4274 578 QVQLVQSGPEVKKPGESLTISCKGSGYDFSNNWIGWVR QMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTLSVDKSIS TAYLQWRSLKASDSGIYYCARQIGGLVCSSESCYFYGM DVWGQGTTVTVSS 268 4275 579 YDFSNNWIG 268 4276 580 TACGACTTTTCCAATAACTGGATCGGC 268 4277 581 IIYPGDSDTRYSPSFQG 268 4278 582 ATCATCTATCCTGGTGACTCTGATACCAGATACAGCCC GTCGTTCCAAGGC 268 4279 583 ARQIGGLVCSSESCYFYGMDV 268 4280 584 GCGAGACAAATTGGCGGTTTGGTTTGTAGCAGTGAGA GCTGCTACTTCTACGGCATGGACGTC 268 4281 585 GACATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGC ATCTGTGGGAGGCAGAGTGACCATCACTTGCCGGGCA AGTCAGAGCATTAGCAACTATTTAAATTGGTATCAAC ACAAACCGGGGAAAGCCCCTGAACTCCTGATCTATGG TGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTC AGTGGCAGTGGATCTGGGACAGACTTCACTCTCACCA TCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTAC TGTCAACAGAGTGACACTACCCCGTTCACTTTCGGCC AGGGGACCAAAGTGGATATCAAA 268 4282 586 DIQLTQSPSSLSASVGGRVTITCRASQSISNYLNWYQHKP GKAPELLIYGASSLQSGVPSRFSGSGSGTDFTLTISSLQPE DFATYYCQQSDTTPFTFGQGTKVDIK 268 4283 587 RASQSISNYLN 268 4284 588 CGGGCAAGTCAGAGCATTAGCAACTATTTAAAT 268 4285 589 GASSLQS 268 4286 590 GGTGCATCCAGTTTGCAAAGT 268 4287 591 QQSDTTPFT 268 4288 592 CAACAGAGTGACACTACCCCGTTCACT 269 4289 593 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCTTGGTAA AGCCGGGGGGGTCCCTTAGACTCTCCTGTGCAGCCTC TGGATTCACTTTCAGTAAGGCCTGGATGAACTGGGTC CGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTGGCC GTATTAGAAGCAAAACTGATGGTGGGACAGCAGACTA CGCGGCACCCGTGAAAGGCAGATTCACCATGTCAAGA GATGATTCAAAAAACACGCTGTATTTGCAAATGAACA GCCTGAAAACCGAGGACACAGCCGTGTATTACTGTGC CACAGATTCTCGCCGACTCTATGATAGTCGTGGTTTTT ATTCAAGTGCTTTTGATGTCTGGGGCCAAGGGACCAC GGTCACCGTCTCCTCA 269 4290 594 QVQLVQSGGGLVKPGGSLRLSCAASGFTFSKAWMNWV RQAPGKGLEWVGRIRSKTDGGTADYAAPVKGRFTMSR DDSKNTLYLQMNSLKTEDTAVYYCATDSRRLYDSRGFY SSAFDVWGQGTTVTVSS 269 4291 595 FTFSKAWMN 269 4292 596 TTCACTTTCAGTAAGGCCTGGATGAAC 269 4293 597 RIRSKTDGGTADYAAPVKG 269 4294 598 CGTATTAGAAGCAAAACTGATGGTGGGACAGCAGACT ACGCGGCACCCGTGAAAGGC 269 4295 599 ATDSRRLYDSRGFYSSAFDV 269 4296 600 GCCACAGATTCTCGCCGACTCTATGATAGTCGTGGTTT TTATTCAAGTGCTTTTGATGTC 269 4297 601 CAGTCTGTCCTGACGCAGCCGCCCTCAGTGTCTGGGG CCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAG CAGCTCCAACATCGGGGCGGGTTATGATGTACACTGG TACCAACACCTTCCAGGAACAGCCCCCAAAGTCCTCA TCTATGGTAACAACAATCGGCCCTCAGGGGTCCCTGA CCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCC TGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGA TTATTACTGCCAGTCCTATGACGACAGCCTGACTGGTT GGGTGTTCGGCGGAGGGACCAAGGTCACCGTCCTA 269 4298 602 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ HLPGTAPKVLIYGNNNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDDSLTGWVFGGGTKVTVL 269 4299 603 TGSSSNIGAGYDVH 269 4300 604 ACTGGGAGCAGCTCCAACATCGGGGCGGGTTATGATG TACAC 269 4301 605 GNNNRPS 269 4302 606 GGTAACAACAATCGGCCCTCA 269 4303 607 QSYDDSLTGWV 269 4304 608 CAGTCCTATGACGACAGCCTGACTGGTTGGGTG 270 4305 609 CAGGTGCAGCTGGTGCAATCTGGACCAGAGGTGAAAA AGCCCGGGGAGTCTCTGACGATCTCCTGTAAGGGTTC TGGATACGACTTTTCCAATAACTGGATCGGCTGGGTG CGCCAGATGCCCGGGAAAGGCCTGGAGTGGATGGGA ATCATCTATCCTGGTGACTCTGATACCAGATACAGCCC GTCGTTCCAAGGCCAGGTCACCCTCTCAGTCGACAAG TCCATTAGTACCGCCTACCTACAGTGGAGGAGCCTGA AGGCCTCGGACAGCGGCATCTACTACTGTGCGAGACA AATTGGCGGTTTGGTTTGTAGCAGTGAGAGCTGCTAC TTCTACGGCATGGACGTCTGGGGCCAAGGGACCACGG TCACCGTCTCCTCA 270 4306 610 QVQLVQSGPEVKKPGESLTISCKGSGYDFSNNWIGWVR QMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTLSVDKSIS TAYLQWRSLKASDSGIYYCARQIGGLVCSSESCYFYGM DVWGQGTTVTVSS 270 4307 611 YDFSNNWIG 270 4308 612 TACGACTTTTCCAATAACTGGATCGGC 270 4309 613 IIYPGDSDTRYSPSFQG 270 4310 614 ATCATCTATCCTGGTGACTCTGATACCAGATACAGCCC GTCGTTCCAAGGC 270 4311 615 ARQIGGLVCSSESCYFYGMDV 270 4312 616 GCGAGACAAATTGGCGGTTTGGTTTGTAGCAGTGAGA GCTGCTACTTCTACGGCATGGACGTC 270 4313 617 GACATCCGGGTGACCCAGTCTCCATCCTCCCTGTCTGC ATCTGTGGGAGGCAGAGTGACCATCACTTGCCGGGCA AGTCAGAGCATTAGCAACTATTTAAATTGGTATCAAC ACAAACCGGGGAAAGCCCCTGAACTCCTGATCTATGG TGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTC AGTGGCAGTGGATCTGGGACAGACTTCACTCTCACCA TCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTAC TGTCAACAGAGTGACACTACCCCGTTCACTTTCGGCC AGGGGACCAAGCTGGAGATCAAA 270 4314 618 DIRVTQSPSSLSASVGGRVTITCRASQSISNYLNWYQHKP GKAPELLIYGASSLQSGVPSRFSGSGSGTDFTLTISSLQPE DFATYYCQQSDTTPFTFGQGTKLEIK 270 4315 619 RASQSISNYLN 270 4316 620 CGGGCAAGTCAGAGCATTAGCAACTATTTAAAT 270 4317 621 GASSLQS 270 4318 622 GGTGCATCCAGTTTGCAAAGT 270 4319 623 QQSDTTPFT 270 4320 624 CAACAGAGTGACACTACCCCGTTCACT 271 4321 625 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCA AGCCTGGGGGGTCCCTGAGACTCTCTTGTGCAGCCTCT GGATTCACCTTCAGTAGTTTTGGCATGCATTGGGTCCG CCAGGCTCCAGGGCAGGGACTGGAGTGGGTCGCATCC ATTACTGGTGGCAGCAGTTACATAAACTACGCAGACT CAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGC CAAGAAGTCACTGTCTCTGCAAATGAAGAACCTGAGA GCCGAGGACACGGCTGAGTATTACTGTGTGCGAGGAG TCCTACCAGGTGATACTGGGGGGGGCTGGTTCGACTC CTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 271 4322 626 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSFGMHWVR QAPGQGLEWVASITGGSSYINYADSVKGRFTISRDNAKK SLSLQMKNLRAEDTAEYYCVRGVLPGDTGGGWFDSWG QGTLVTVSS 271 4323 627 FTFSSFGMH 271 4324 628 TTCACCTTCAGTAGTTTTGGCATGCAT 271 4325 629 SITGGSSYINYADSVKG 271 4326 630 TCCATTACTGGTGGCAGCAGTTACATAAACTACGCAG ACTCAGTGAAGGGC 271 4327 631 VRGVLPGDTGGGWFDS 271 4328 632 GTGCGAGGAGTCCTACCAGGTGATACTGGGGGGGGCT GGTTCGACTCC 271 4329 633 CAGTCTGTGCTGACGCAGCCGCCCTCAATGTCTGGGG CCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAC CAGCTCCAACATCGGGGCGGGTTATGATGTACAGTGG TATCAGCAGTTTCCAGGAACAGCCCCCAAACTCCTCA TCTCTGGTAACAACAATCGGCCCTCAGGGGTCCCTGA CCGATTCTCTGGCTCCAAGTCTGGCGCCTCAGCCTCCC TGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGA TTATTACTGCCAGTCCTATGACTACAGCCTGAATTGGG TGTTCGGCGGAGGGACCAAGCTGACCGTCCTA 271 4330 634 QSVLTQPPSMSGAPGQRVTISCTGTSSNIGAGYDVQWYQ QFPGTAPKLLISGNNNRPSGVPDRFSGSKSGASASLAITG LQAEDEADYYCQSYDYSLNWVFGGGTKLTVL 271 4331 635 TGTSSNIGAGYDVQ 271 4332 636 ACTGGGACCAGCTCCAACATCGGGGCGGGTTATGATG TACAG 271 4333 637 GNNNRPS 271 4334 638 GGTAACAACAATCGGCCCTCA 271 4335 639 QSYDYSLNWV 271 4336 640 CAGTCCTATGACTACAGCCTGAATTGGGTG 272 4337 641 CAGGTCCAGCTTGTACAGTCTGGAGCAGAGGTGAAAA AGCCCGGGGAGTCTCTGAAGATCTCCTGTAAGGGTTC TGGATACAGCTTTAGCAGTTTCTGGATCGGCTGGGTG CGCCAGATGCCCGGGAAAGGCCTGGAGTGGATGGGC ATCATATATCCTGGTGACTCTGATACCAGATATAGCCC GTCTTTCCAAGGCCAGGTCACCATGTCAGCCGACACG TCCATAAACACCGCCTACCTGCAGTGGAACAGCGTGA AGGCCTCGGACACCGCCATTTATTACTGTGCGAGACT TCCAGTTGGTAGTTATTATTACTTCAATCTCTGGGGCC GTGGCACCCTGGTCACCGTCTCCTCA 272 4338 642 QVQLVQSGAEVKKPGESLKISCKGSGYSFSSFWIGWVRQ MPGKGLEWMGIIYPGDSDTRYSPSFQGQVTMSADTSINT AYLQWNSVKASDTAIYYCARLPVGSYYYFNLWGRGTL VTVSS 272 4339 643 YSFSSFWIG 272 4340 644 TACAGCTTTAGCAGTTTCTGGATCGGC 272 4341 645 IIYPGDSDTRYSPSFQG 272 4342 646 ATCATATATCCTGGTGACTCTGATACCAGATATAGCCC GTCTTTCCAAGGC 272 4343 647 ARLPVGSYYYFNL 272 4344 648 GCGAGACTTCCAGTTGGTAGTTATTATTACTTCAATCT C 272 4345 649 GAAATTGTGATGACACAGTCTCCAGCCACCCTGTCTG TGTCTCCAGGGGAAAGCGCCACCCTATTTTGCAGGGC CAGTCAGAGTATTAGTAGCGACTTAGCCTGGTACCAG CAGAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATG ATGCATCCACCAGGGCCACTGGTGTCCCTGCCAGGTT CAGTGCCACTGGGTCTGAGGCAGAGTTCACTCTCACC ATCAGCGGCCTGCAGTCTGAAGATTTTGCAGTTTATTA CTGTCAGCAGTATAATAACTGGCTTTCGTGGACGTTCG GCCAAGGGACCAAGCTGGAGATCAAA 272 4346 650 EIVMTQSPATLSVSPGESATLFCRASQSISSDLAWYQQRP GQAPRLLIYDASTRATGVPARFSATGSEAEFTLTISGLQS EDFAVYYCQQYNNWLSWTFGQGTKLEIK 272 4347 651 RASQSISSDLA 272 4348 652 AGGGCCAGTCAGAGTATTAGTAGCGACTTAGCC 272 4349 653 DASTRAT 272 4350 654 GATGCATCCACCAGGGCCACT 272 4351 655 QQYNNWLSWT 272 4352 656 CAGCAGTATAATAACTGGCTTTCGTGGACG 273 4353 657 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGAG AAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTC TCGTGGCTCCATCAGAATTGGTGGTTACTTCTGGAGTT GGATCCGCCAGCACCCAGGGAAGGGTCTGGAGTGGCT TGGATACATCTCTAACGATGGGGCCACCGACTACAAC CCGTCCCTCAGGAGTCGACTTGCCATATCAGCAGACA CATCTAAGAACCAGTTTTCCCTGACCCTGAGGTCTGTG ACTGCCGCGGACACGGCCATCTATTACTGTGCGAGAA CTTCTTATGCAGGGCGCATGCTCGACCGCTGGGGCCA GGGAATCCTGGTCACCGTCTCCTCA 273 4354 658 QVQLQESGPGLEKPSQTLSLTCTVSRGSIRIGGYFWSWIR QHPGKGLEWLGYISNDGATDYNPSLRSRLAISADTSKNQ FSLTLRSVTAADTAIYYCARTSYAGRMLDRWGQGILVT VSS 273 4355 659 GSIRIGGYFWS 273 4356 660 GGCTCCATCAGAATTGGTGGTTACTTCTGGAGT 273 4357 661 YISNDGATDYNPSLRS 273 4358 662 TACATCTCTAACGATGGGGCCACCGACTACAACCCGT CCCTCAGGAGT 273 4359 663 ARTSYAGRMLDR 273 4360 664 GCGAGAACTTCTTATGCAGGGCGCATGCTCGACCGC 273 4361 665 GACATCCGGGTGACCCAGTCTCCAGTCTCCCTGCCCGT CACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGGTCT AGTCAGAGTCTCCTGCATAGTAATGGAAACAACTATT TGGATTGGTACCTGCAGAAGCCAGGGCAGTCTCCACA ACTCCTGATCTATATGGGTTCTTATCGGGCCTCCGGGG TCCCTGACAGGTTCAGCGGCAGTGGATCAGGCACAGA TTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGGAT GTTGGTGTTTATTACTGCATGCAAGGTCTACAAATTCC TTGGACGTTCGGCCAAGGGACCAAGCTGGAGATCAAA 273 4362 666 DIRVTQSPVSLPVTPGEPASISCRSSQSLLHSNGNNYLDW YLQKPGQSPQLLIYMGSYRASGVPDRFSGSGSGTDFTLKI SRVEAEDVGVYYCMQGLQIPWTFGQGTKLEIK 273 4363 667 RSSQSLLHSNGNNYLD 273 4364 668 AGGTCTAGTCAGAGTCTCCTGCATAGTAATGGAAACA ACTATTTGGAT 273 4365 669 MGSYRAS 273 4366 670 ATGGGTTCTTATCGGGCCTCC 273 4367 671 MQGLQIPWT 273 4368 672 ATGCAAGGTCTACAAATTCCTTGGACG 274 4369 673 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCGTGGTCC AGCCTGGGAGGTCCCTCAGACTCTCCTGTGCAGCCTCT GGATTCACCTTCAGTAGCTATGCCATGCACTGGGTCC GCCAGACTCCAGACAAGGGGCTGGAGTGGGTGGCACT TATATCCGATGATGGAAGAAATGAATATTATGCAGAT TCCGTGCAGGGCCGATTCACCATCTCCAGAGACAAAT CCAAGAACACGCTGCATCTGGAAATGAACAGCCTGAG AGCTGAGGACACGGCTGTTTATTACTGTGCGAAAGTA CGAAATGAGGCGTGGGAGCTCCTGGGTAATGATGATG CTCTTGATGTCTGGGGCCAAGGGACAATGGTCACCGT CTCTTCA 274 4370 674 EVQLLESGGGVVQPGRSLRLSCAASGFTFSSYAMHWVR QTPDKGLEWVALISDDGRNEYYADSVQGRFTISRDKSK NTLHLEMNSLRAEDTAVYYCAKVRNEAWELLGNDDAL DVWGQGTMVTVSS 274 4371 675 FTFSSYAMH 274 4372 676 TTCACCTTCAGTAGCTATGCCATGCAC 274 4373 677 LISDDGRNEYYADSVQG 274 4374 678 CTTATATCCGATGATGGAAGAAATGAATATTATGCAG ATTCCGTGCAGGGC 274 4375 679 AKVRNEAWELLGNDDALDV 274 4376 680 GCGAAAGTACGAAATGAGGCGTGGGAGCTCCTGGGT AATGATGATGCTCTTGATGTC 274 4377 681 CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGCGG CCCCAGGACAGAAAGTCACCATCTCCTGCTCTGGAAC TAGCTTCAACATTGGCAGTAATTACGTATCCTGGTACC AGCTACTCCCAGGAACAGCCCCCAAACTCCTCATTTTT GACAATTATAAGCGACCCTCAGGGATTCCTGACCGAT TCTCTGGCTCCTGGTCTGGCACGTCAGCCACCCTGGCC ATCAGCGGACTCCAGACTGGGGACGAGGCCGAATACT TCTGCGGAACTTGGGACACCAGCCTGAGAGCTGGAGT GTTCGGCGGAGGGACCAAGCTCACCGTCCTA 274 4378 682 QSVLTQPPSVSAAPGQKVTISCSGTSFNIGSNYVSWYQLL PGTAPKLLIFDNYKRPSGIPDRFSGSWSGTSATLAISGLQT GDEAEYFCGTWDTSLRAGVFGGGTKLTVL 274 4379 683 SGTSFNIGSNYVS 274 4380 684 TCTGGAACTAGCTTCAACATTGGCAGTAATTACGTATC C 274 4381 685 DNYKRPS 274 4382 686 GACAATTATAAGCGACCCTCA 274 4383 687 GTWDTSLRAGV 274 4384 688 GGAACTTGGGACACCAGCCTGAGAGCTGGAGTG 275 4385 689 CAGGTCCAGCTGGTGCAGTCTGGGTCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAGGCTCTCCTGCAAGGTTGC CGGTTACAGCCTCAGTGAGTTATCCATGCACTGGGTG CGACAGTCTCCTGGAAAAGGGCTTGAGTGGTTGGGAG CTTTTGACCATGAAGATGCTGAAGCAATCTATGCACC GAGGTTCCAGGGCAGAATCACCATGACCGCGGACACA TCTACGGACACAGCCTACATGGAACTGAGCAGCCTGA GATCTGAGGACACGGCCGTTTATTACTGTGCAACACC GACCCCAGTTGGAGCTACGGACTACTGGGGCCAGGGA ACCCTGGTCACCGTCTCCTCA 275 4386 690 QVQLVQSGSEVKKPGASVRLSCKVAGYSLSELSMHWVR QSPGKGLEWLGAFDHEDAEAIYAPRFQGRITMTADTSTD TAYMELSSLRSEDTAVYYCATPTPVGATDYWGQGTLVT VSS 275 4387 691 YSLSELSMH 275 4388 692 TACAGCCTCAGTGAGTTATCCATGCAC 275 4389 693 AFDHEDAEAIYAPRFQG 275 4390 694 GCTTTTGACCATGAAGATGCTGAAGCAATCTATGCAC CGAGGTTCCAGGGC 275 4391 695 ATPTPVGATDY 275 4392 696 GCAACACCGACCCCAGTTGGAGCTACGGACTAC 275 4393 697 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCA AGTCAGAGTATTAGTAGTTATTTAAATTGGTATCAAC AAAAACCAGGAAAAGCCCCTAAGCTCCTGATCTATGC TGCATCCAGTTTGCAAAGGGGGGGCCCATCAAGATTC AGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCA TCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTAT TGTCAACAGAGTTACATTATTCCGTACACTTTTGGCCA GGGGACCAAAGTGGATATCAAA 275 4394 698 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKP GKAPKLLIYAASSLQRGGPSRFSGSGSGTDFTLTISSLQPE DFATYYCQQSYIIPYTFGQGTKVDIK 275 4395 699 RASQSISSYLN 275 4396 700 CGGGCAAGTCAGAGTATTAGTAGTTATTTAAAT 275 4397 701 AASSLQR 275 4398 702 GCTGCATCCAGTTTGCAAAGG 275 4399 703 QQSYIIPYT 275 4400 704 CAACAGAGTTACATTATTCCGTACACT 276 4401 705 CAGGTGCAGCTGCAGGAGTCCGGCCCAGGACGGGTG AAGCCTTCGGAGACCCTGTCCCTCACCTGCAGTGTCG CTGATGGCTCAATCAGTAGTGGTCATTACTACTGGGG CTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGG ATTGCGACAATCCATGATAGTGGGGCCACGTACTACA ACCCGTCCCTCCAGAGTCGAGTCACCATATCCGTAGA CACGTCCAAGAACCAGTTCTCCCTGAAAGTGAATTCT GTGACCGCCGCAGACACGGCTGTCTATTACTGTGCGA GTCGAAGGGGCAGTGGCTGGTTTTTCGACTCCTGGGG CCAGGGAACCCTGGTCACCGTCTCCTCA 276 4402 706 QVQLQESGPGRVKPSETLSLTCSVADGSISSGHYYWGW VRQPPGKGLEWIATIHDSGATYYNPSLQSRVTISVDTSK NQFSLKVNSVTAADTAVYYCASRRGSGWFFDSWGQGT LVTVSS 276 4403 707 GSISSGHYYWG 276 4404 708 GGCTCAATCAGTAGTGGTCATTACTACTGGGGC 276 4405 709 TIHDSGATYYNPSLQS 276 4406 710 ACAATCCATGATAGTGGGGCCACGTACTACAACCCGT CCCTCCAGAGT 276 4407 711 ASRRGSGWFFDS 276 4408 712 GCGAGTCGAAGGGGCAGTGGCTGGTTTTTCGACTCC 276 4409 713 GATATTGTGCTGACTCAGTCTCCAGCCACCCTGTCTGT GTCTCCAGGGGAAAGAGTCACCCTCTCCTGCAGGGCC AGTCACAGTGTTAACTACAATTTAGCCTGGTACCAGC AGAAACCTGGTCAGGCTCCCAGGCTCCTCATCTATGG TTCATCTACCAGGGCCACTGGTCTCCCAGCCAGGTTCA GTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCAT CAGCAGCCTGCAGTCTGAAGATTTTGCAATTTATTACT GTCAGCAGTATAATAACTGGCCTCCGGGAGGCACTTT TGGCCAGGGGACCAAGGTGGAAATCAAA 276 4410 714 DIVLTQSPATLSVSPGERVTLSCRASHSVNYNLAWYQQK PGQAPRLLIYGSSTRATGLPARFSGSGSGTEFTLTISSLQS EDFAIYYCQQYNNWPPGGTFGQGTKVEIK 276 4411 715 RASHSVNYNLA 276 4412 716 AGGGCCAGTCACAGTGTTAACTACAATTTAGCC 276 4413 717 GSSTRAT 276 4414 718 GGTTCATCTACCAGGGCCACT 276 4415 719 QQYNNWPPGGT 276 4416 720 CAGCAGTATAATAACTGGCCTCCGGGAGGCACT 277 4417 721 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCCTGGTCA AGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTC TGGATTCACCTTCAGTAGCTATAGCATGAACTGGGTC CGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTAGTAGTAGTAGTAGTTACATATACTACGCAGA CTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAAC GCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGA GAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGA TTGGCCGAATAGCAGCTCGTCGCCGAACTGGTTCGAC CCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 277 4418 722 EVQLLESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVR QAPGKGLEWVSSISSSSSYIYYADSVKGRFTISRDNAKNS LYLQMNSLRAEDTAVYYCARDWPNSSSSPNWFDPWGQ GTLVTVSS 277 4419 723 FTFSSYSMN 277 4420 724 TTCACCTTCAGTAGCTATAGCATGAAC 277 4421 725 SISSSSSYIYYADSVKG 277 4422 726 TCCATTAGTAGTAGTAGTAGTTACATATACTACGCAG ACTCAGTGAAGGGC 277 4423 727 ARDWPNSSSSPNWFDP 277 4424 728 GCGAGAGATTGGCCGAATAGCAGCTCGTCGCCGAACT GGTTCGACCCC 277 4425 729 CAGTCTGTCCTGACGCAGCCGCCCTCAGTGTCTGGGG CCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAG CAGCTCCAACATCGGGGCAGGTTATGATGTACACTGG TACCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTCA TCTATGGTAACAGCAATCGGCCCTCAGGGGTCCCTGA CCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCC TGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGA TTATTACTGCCAGTCCTATGACAGCAGCCTGAGTGGTT TTTATGTCTTCGGAACTGGGACCAAGCTCACCGTCCTA 277 4426 730 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSSLSGFYVFGTGTKLTVL 277 4427 731 TGSSSNIGAGYDVH 277 4428 732 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATG TACAC 277 4429 733 GNSNRPS 277 4430 734 GGTAACAGCAATCGGCCCTCA 277 4431 735 QSYDSSLSGFYV 277 4432 736 CAGTCCTATGACAGCAGCCTGAGTGGTTTTTATGTC 278 4433 737 CAGGTCCAGCTGGTACAGTCTGGGGCAGAGGTGAAAA AGCCCGGGGAGTCTCTGAAGATCTCCTGTCAGGGTTC TGGATACAGCTTTAGCAGTTTCTGGATCGTCTGGGTGC GCCAGATGCCCGGGAAAGGCCTGGAGTGGATGGGGA GCATCTATCCTGGTGACTCTGACACCAGATACACCCC GTCCTTCCAAGGCCAGGTCACCATCTCAGCCGACAAG TCCACCAGCACCGCCTATTTGCAGTGGAACAGCCTGA AGCCCTCGGACACCGCCATGTATTACTGTGCGAGGTG TAGTCTCAGCTGCGACTACTACGGAGTGAACCTCTGG GGCCAAGGGACCACGGTCACCGTCTCCTCA 278 4434 738 QVQLVQSGAEVKKPGESLKISCQGSGYSFSSFWIVWVRQ MPGKGLEWMGSIYPGDSDTRYTPSFQGQVTISADKSTST AYLQWNSLKPSDTAMYYCARCSLSCDYYGVNLWGQGT TVTVSS 278 4435 739 YSFSSFWIV 278 4436 740 TACAGCTTTAGCAGTTTCTGGATCGTC 278 4437 741 SIYPGDSDTRYTPSFQG 278 4438 742 AGCATCTATCCTGGTGACTCTGACACCAGATACACCC CGTCCTTCCAAGGC 278 4439 743 ARCSLSCDYYGVNL 278 4440 744 GCGAGGTGTAGTCTCAGCTGCGACTACTACGGAGTGA ACCTC 278 4441 745 CAGTCTGTGGTGACGCAGCCGCCCTCAGTGTCTGGGG CCCCAGGACAGAGGGTCACCATCTCCTGCTCTGGGAG CAGCTCCAACATCGGGGCACGTTCTGATGTACACTGG TACCAGCAGCTTCCAGGAAAAGCCCCCAAACTCCTCA TCTATGGTAACACCAATCGGCCCTTAGGGGTCCCTGA CCGATTCTCTGGCTCCACGTCTGGCACCTCAGCCTCCC TGGCCATCTCTGGGCTCCAGGCTGAGGATGAGGGATA TTATTACTGTCAGTCCTATGACAGCAGCCTGAGTGGTT TTTATGTCTTCGGAACTGGGACCAAGCTCACCGTCCTA 278 4442 746 QSVVTQPPSVSGAPGQRVTISCSGSSSNIGARSDVHWYQ QLPGKAPKLLIYGNTNRPLGVPDRFSGSTSGTSASLAISG LQAEDEGYYYCQSYDSSLSGFYVFGTGTKLTVL 278 4443 747 SGSSSNIGARSDVH 278 4444 748 TCTGGGAGCAGCTCCAACATCGGGGCACGTTCTGATG TACAC 278 4445 749 GNTNRPL 278 4446 750 GGTAACACCAATCGGCCCTTA 278 4447 751 QSYDSSLSGFYV 278 4448 752 CAGTCCTATGACAGCAGCCTGAGTGGTTTTTATGTC 279 4449 753 CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCC AGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTC TGGATTCCCCTTCAGTCTCTATGCCATGCACTGGGTCC GCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCATT TATATCATATGATGGAAGTAATAAATACTATGCAGAC TCCGTGAAGGGCCGATTCACCATCTCCAGAGACAGTT CCAAGAACACGCTGTATCTGCAAATGGACAGCCTGAC ACCTGAAGACACGGCTGTGTATTACTGTGCGAAACCT ATAGTGGGGCCTACAACGGGTTACTTTGACTACTGGG GCCCGGGAACCCTGGTCACCGTCTCCTCA 279 4450 754 QVQLVESGGGVVQPGRSLRLSCAASGFPFSLYAMHWVR QAPGKGLEWVAFISYDGSNKYYADSVKGRFTISRDSSKN TLYLQMDSLTPEDTAVYYCAKPIVGPTTGYFDYWGPGT LVTVSS 279 4451 755 FPFSLYAMH 279 4452 756 TTCCCCTTCAGTCTCTATGCCATGCAC 279 4453 757 FISYDGSNKYYADSVKG 279 4454 758 TTTATATCATATGATGGAAGTAATAAATACTATGCAG ACTCCGTGAAGGGC 279 4455 759 AKPIVGPTTGYFDY 279 4456 760 GCGAAACCTATAGTGGGGCCTACAACGGGTTACTTTG ACTAC 279 4457 761 GAAATTGTGTTGACTCAGTCTCCAGCCACCCTGTCTTT GTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC AGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAAC AGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGA TGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTC AGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCA TCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTAC TGTCAGCAGCGTAGCAACTGGTACACTTTTGGCCAGG GGACCAAGGTGGAAATCAAA 279 4458 762 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKP GQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPE DFAVYYCQQRSNWYTFGQGTKVEIK 279 4459 763 RASQSVSSYLA 279 4460 764 AGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCC 279 4461 765 DASNRAT 279 4462 766 GATGCATCCAACAGGGCCACT 279 4463 767 QQRSNWYT 279 4464 768 CAGCAGCGTAGCAACTGGTACACT 280 4465 769 GAGGTGCAGCTGGTGGAGTCTGGGGCTGAGGTGAAG AAGCCTGGGGCCTCAGTGAAGGTCTCCTGCCAGACTT CTGGTTACACCTTTAGTCATTTCGGTGTCACCTGGATA CGACAGGCCCCAGGACAAGGGCTTGAGTGGCTGGGAT GGATCAGCGCTTACAATGGTAACACAGACTATGCAGA CAAACTGCAGGGCAGACTCACCATGACCACAGACACA TCCACGAACACCGCCTACATGGAATTGAGGAGCCTCA GATCTGACGACACGGCCGTCTATTACTGTGCGAGAGA TCCCCCCGCATCAGCTGCTGCGATGCTTGACTACTGGG GCCAGGGAACCCTGGTCACCGTCTCCTCA 280 4466 770 EVQLVESGAEVKKPGASVKVSCQTSGYTFSHFGVTWIR QAPGQGLEWLGWISAYNGNTDYADKLQGRLTMTTDTS TNTAYMELRSLRSDDTAVYYCARDPPASAAAMLDYWG QGTLVTVSS 280 4467 771 YTFSHFGVT 280 4468 772 TACACCTTTAGTCATTTCGGTGTCACC 280 4469 773 WISAYNGNTDYADKLQG 280 4470 774 TGGATCAGCGCTTACAATGGTAACACAGACTATGCAG ACAAACTGCAGGGC 280 4471 775 ARDPPASAAAMLDY 280 4472 776 GCGAGAGATCCCCCCGCATCAGCTGCTGCGATGCTTG ACTAC 280 4473 777 GATATTGTGATGACTCAGTCTCCACTCTCCCTGGCCGT CACCCTTGGACAGCCGGCCTCCATCTCCTGCAAGTCTA GTCAAGGCCTCGAATACACTGATGGAAACACCTACTT GAGTTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGG CGCCTCATTTATAAGATTTCTAACCGGGACTCTGGGGT TCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGAT TTCACACTGAGAATCAGCAGGGTGGAGGCTGAGGATG TTGGGGTTTATTACTGCATGCAAGGTACACACGGGCG GGGAATCTCTTTCGGTCCTGGGACCAAAGTGGATATC AAA 280 4474 778 DIVMTQSPLSLAVTLGQPASISCKSSQGLEYTDGNTYLS WFQQRPGQSPRRLIYKISNRDSGVPDRFSGSGSGTDFTLR ISRVEAEDVGVYYCMQGTHGRGISFGPGTKVDIK 280 4475 779 KSSQGLEYTDGNTYLS 280 4476 780 AAGTCTAGTCAAGGCCTCGAATACACTGATGGAAACA CCTACTTGAGT 280 4477 781 KISNRDS 280 4478 782 AAGATTTCTAACCGGGACTCT 280 4479 783 MQGTHGRGIS 280 4480 784 ATGCAAGGTACACACGGGCGGGGAATCTCT 281 4481 785 CAGGTGCAGCTGGTGCAGTCTGGGGCTGAAGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTC TGGATACACCTTCACCGACTACTTTATACACTGGGTGC GCCAGGCCCCTGGAGAAGGGCTTGAGTGGATGGGTTG GGTCAACCCTCTCAGTGACAACACAAAATATTCACAG AAGTTTCAGGGCAGGGTCACCATGAGCACGGACACGT CCATCACCACGGCCTACATGTACCTGAGCAGGCTGCG ATTTGACGACACGGCCGTGTATTTTTGTGCGAGCCAAT CTTCCCCCTATACCCCGGGCGCTCTGGACGTCTGGGGC CAAGGGACCACGGTCACCGTCTCCTCA 281 4482 786 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYFIHWVR QAPGEGLEWMGWVNPLSDNTKYSQKFQGRVTMSTDTS ITTAYMYLSRLRFDDTAVYFCASQSSPYTPGALDVWGQ GTTVTVSS 281 4483 787 YTFTDYFIH 281 4484 788 TACACCTTCACCGACTACTTTATACAC 281 4485 789 WVNPLSDNTKYSQKFQG 281 4486 790 TGGGTCAACCCTCTCAGTGACAACACAAAATATTCAC AGAAGTTTCAGGGC 281 4487 791 ASQSSPYTPGALDV 281 4488 792 GCGAGCCAATCTTCCCCCTATACCCCGGGCGCTCTGG ACGTC 281 4489 793 GACATCCAGTTGACCCAGTCTCCATCCTCCCTGCCTGC ATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCA AGTCAGAACATTGGGAACAATTTAGCTTGGTATCAGC AGAAAGCAGGAAGAGCCCCCAAACTCCTGATCTATAG TGCGTCTAATTTCCATAGTGGGGTCCCATCAAGATTCA TTGGCAGTGGATCTGGGACAGTTTTCACTCTCACCATC AGCAGTCTGCAACCTGAAGATTTTGCAACCTACTTCTG TCAACAGAGTTTCACTCCCCAATTCACTTTCGGCCCTG GGACCAAGGTGGAAATCAAA 281 4490 794 DIQLTQSPSSLPASVGDRVTITCRASQNIGNNLAWYQQK AGRAPKLLIYSASNFHSGVPSRFIGSGSGTVFTLTISSLQP EDFATYFCQQSFTPQFTFGPGTKVEIK 281 4491 795 RASQNIGNNLA 281 4492 796 CGGGCAAGTCAGAACATTGGGAACAATTTAGCT 281 4493 797 SASNFHS 281 4494 798 AGTGCGTCTAATTTCCATAGT 281 4495 799 QQSFTPQFT 281 4496 800 CAACAGAGTTTCACTCCCCAATTCACT 282 4497 801 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGA GGCCTGGGTCCTCGGTGAGGGTCTCCTGCAAGGCTTC TGGAGGCACCTTCAGGAAGTATGCTATCAGTTGGGTG CGACAGGCCCGTGGACAAGGGCTTGAGTGGATGGGA GGCATCATCCCTATGTCCGGACCACCAAGCTACGCAC AGAAGTTTCAGGGCAGAGTCACGATTACCGCGGACGA ATCCACGAGCACAGTCTACATGGAGCTGAGCAGCCTG AGATTTGAGGACACGGCCGTGTATTTCTGTGCGAGGG ATATCGAGTGGTTCGTACTCATGGACCCTATCACATCC TACTACCCTATGGACGTCTGGGGCCAAGGGACCACGG TCACCGTCTCCTCA 282 4498 802 QVQLVQSGAEVKRPGSSVRVSCKASGGTFRKYAISWVR QARGQGLEWMGGIIPMSGPPSYAQKFQGRVTITADESTS TVYMELSSLRFEDTAVYFCARDIEWFVLMDPITSYYPMD VWGQGTTVTVSS 282 4499 803 GTFRKYAIS 282 4500 804 GGCACCTTCAGGAAGTATGCTATCAGT 282 4501 805 GIIPMSGPPSYAQKFQG 282 4502 806 GGCATCATCCCTATGTCCGGACCACCAAGCTACGCAC AGAAGTTTCAGGGC 282 4503 807 ARDIEWFVLMDPITSYYPMDV 282 4504 808 GCGAGGGATATCGAGTGGTTCGTACTCATGGACCCTA TCACATCCTACTACCCTATGGACGTC 282 4505 809 CAGTCTGTGGTGACCCAGGAGCCCTCACTGACTGTGT CCCCAGGAGGGACAGTCACTCTCACCTGTGGCTCCAG CACTGGAGGTGTCACCAGTGGTCATCATACATACTGG TTCCAGCAGAAGCCTGGCCAAGCCCCCAGGACACTGA TCTATGATACGACCAACACACACTCCTGGACACCAGC CCGGTTCGCAGGCTCCCTCCTTGGGGGCAAAGCTGCC CTGACCCTTTCGGGTGCGCAGCCTGAGGATGAGGCTG ACTATTACTGCCTCCTCTCCTATAGTGGTGCGCGGCCG GTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA 282 4506 810 QSVVTQEPSLTVSPGGTVTLTCGSSTGGVTSGHHTYWFQ QKPGQAPRTLIYDTTNTHSWTPARFAGSLLGGKAALTLS GAQPEDEADYYCLLSYSGARPVFGGGTKLTVL 282 4507 811 GSSTGGVTSGHHTY 282 4508 812 GGCTCCAGCACTGGAGGTGTCACCAGTGGTCATCATA CATAC 282 4509 813 DTTNTHS 282 4510 814 GATACGACCAACACACACTCC 282 4511 815 LLSYSGARPV 282 4512 816 CTCCTCTCCTATAGTGGTGCGCGGCCGGTG 283 4513 817 CAGGTGCAGCTGGTGCAGTCTGGGGGAGGCTTGGTCA AGCCTGGAGGGTCCCTGAGACTCTCCTGTGCAGCCTC TGGATTCACCTTCAATGATTACTACATGAATTGGATCC GCCAGGCTCCAGGGAAGGGGCTGGAATGGGTTTCATA CATTAGTAGTAGTGGTGAGACCAAATACTACGCAGAC TCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACG CCAAGAACTCACTGTATCTGGAAATGAACAGCCTGAG AGTCGAGGACACGGCCGTCTACTACTGTGCGAGAGAC GCGGTCATTGTAGTAGGACCGGTTGCTGTTCACTACC AATACTACGCGGACGTCTGGGGCAAAGGGACCACGGT CACCGTCTCTTCA 283 4514 818 QVQLVQSGGGLVKPGGSLRLSCAASGFTFNDYYMNWIR QAPGKGLEWVSYISSSGETKYYADSVKGRFTISRDNAKN SLYLEMNSLRVEDTAVYYCARDAVIVVGPVAVHYQYY ADVWGKGTTVTVSS 283 4515 819 FTFNDYYMN 283 4516 820 TTCACCTTCAATGATTACTACATGAAT 283 4517 821 YISSSGETKYYADSVKG 283 4518 822 TACATTAGTAGTAGTGGTGAGACCAAATACTACGCAG ACTCTGTGAAGGGC 283 4519 823 ARDAVIVVGPVAVHYQYYADV 283 4520 824 GCGAGAGACGCGGTCATTGTAGTAGGACCGGTTGCTG TTCACTACCAATACTACGCGGACGTC 283 4521 825 CAGCCAGTGCTGACTCAGCCACCCTCAGCGTCTGGGA CCCCCGGGCAGAGGGTCACCATCTCTTGTTCTGGAAG CACCTCCAACATCGGAAGTAACACTGTACACTGGTAC CAGCAACTCCCAGGAACGGCCCCCAGACTCCTCATCT ATGTTATTAATCAGCGGCCCTCAGGGGTCCCAGACCG ATTCTCCGGCTCCAAGTCTGGCACCTCAGCCTCCCTGG CCATCAGTGGGCTCCAGTCTGAGGATGAGGCTGATTA TTACTGTGCAGCATGGGATGACAGCCTGAATGGTCCG GTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA 283 4522 826 QPVLTQPPSASGTPGQRVTISCSGSTSNIGSNTVHWYQQL PGTAPRLLIYVINQRPSGVPDRFSGSKSGTSASLAISGLQS EDEADYYCAAWDDSLNGPVFGGGTKLTVL 283 4523 827 SGSTSNIGSNTVH 283 4524 828 TCTGGAAGCACCTCCAACATCGGAAGTAACACTGTAC AC 283 4525 829 VINQRPS 283 4526 830 GTTATTAATCAGCGGCCCTCA 283 4527 831 AAWDDSLNGPV 283 4528 832 GCAGCATGGGATGACAGCCTGAATGGTCCGGTG 284 4529 833 CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGA AGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCCTC TGGAGGCACCTTCAGCGGCTACCATATCAGCTGGGTG CGACAGGCCCCTGGACAAGGGCTCGAGTGGATGGGA GGGATCATCCATCTATTTGGGACAGTTAACTACGCTCC GAAGTTCCAGGGCAGAGTCACGATCACCGCGGACGCA TCCACGGGCACAGCCTACATGGAGTTAAACAGCCTGA TGTCTGAAGACACGGCCGTTTATTATTGTGCGAGAGA TGCCTACGAAGTGTGGACTGGTTCTTATCTCCCCCCTT TTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTC CTCA 284 4530 834 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSGYHISWVR QAPGQGLEWMGGIIHLFGTVNYAPKFQGRVTITADAST GTAYMELNSLMSEDTAVYYCARDAYEVWTGSYLPPFD YWGQGTLVTVSS 284 4531 835 GTFSGYHIS 284 4532 836 GGCACCTTCAGCGGCTACCATATCAGC 284 4533 837 GIIHLFGTVNYAPKFQG 284 4534 838 GGGATCATCCATCTATTTGGGACAGTTAACTACGCTCC GAAGTTCCAGGGC 284 4535 839 ARDAYEVWTGSYLPPFDY 284 4536 840 GCGAGAGATGCCTACGAAGTGTGGACTGGTTCTTATC TCCCCCCTTTTGACTAC 284 4537 841 GAAATTGTGTTGACACAGTCTCCAGGCACCCTGTCTTT GTCTCCCGGGGAAAGAGTCACCCTCTCCTGCAGGGCC AGTCAGACTGTTACAAGCAGCTACTTAGCCTGGTACC AGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTA TGGTGCATTCACCAGGGCCACTGACATCCCAGACAGG TTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCA CCATCAGCAGACTGGAGCCTGAAGATTCTGCAGTATA TTATTGTCAGCAGTATGGTAGCTCATTCCTCACTTTCG GCGGAGGGACCAAAGTGGATATCAAA 284 4538 842 EIVLTQSPGTLSLSPGERVTLSCRASQTVTSSYLAWYQQ KPGQAPRLLIYGAFTRATDIPDRFSGSGSGTDFTLTISRLE PEDSAVYYCQQYGSSFLTFGGGTKVDIK 284 4539 843 RASQTVTSSYLA 284 4540 844 AGGGCCAGTCAGACTGTTACAAGCAGCTACTTAGCC 284 4541 845 GAFTRAT 284 4542 846 GGTGCATTCACCAGGGCCACT 284 4543 847 QQYGSSFLT 284 4544 848 CAGCAGTATGGTAGCTCATTCCTCACT 285 4545 849 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGCAAA AGCCCGGGCGGTCCCTGCGACTCTCATGTTCAGCTTCT GGATTCACCTTTGGTGATTATGCTATGAGCTGGTTCCG CCAGGCTCCAGGGAAGGGCCTGGAGTGGGTTGGTTTC ATTAGAAGTAAAGCTTATGTTGGGACCGCAGAATACG CCGCGTCTGTGAAAGGCAGATTCACCATCTCAAGAGA TGATTCCAAAAGCATCGCCTATCTGCACATGAACAGC CTGAAGACCGAGGACACAGCCGTGTATTACTGTACTA GAGATGATATTTTGACTGGTTTTTATGACCGCTCTTAC TATTACGGTATACACGTCTGGGGCCAAGGGACCACGG TCACCGTCTCCTCA 285 4546 850 EVQLVESGGGLQKPGRSLRLSCSASGFTFGDYAMSWFR QAPGKGLEWVGFIRSKAYVGTAEYAASVKGRFTISRDD SKSIAYLHMNSLKTEDTAVYYCTRDDILTGFYDRSYYYG IHVWGQGTTVTVSS 285 4547 851 FTFGDYAMS 285 4548 852 TTCACCTTTGGTGATTATGCTATGAGC 285 4549 853 FIRSKAYVGTAEYAASVKG 285 4550 854 TTCATTAGAAGTAAAGCTTATGTTGGGACCGCAGAAT ACGCCGCGTCTGTGAAAGGC 285 4551 855 TRDDILTGFYDRSYYYGIHV 285 4552 856 ACTAGAGATGATATTTTGACTGGTTTTTATGACCGCTC TTACTATTACGGTATACACGTC 285 4553 857 GAAATTGTAATGACGCAGTCTCCAGTCACCCTGTCTGT GTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC AGTCAGAGTGTTAACAGCAACTTAGCCTGGTACCAGA AGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATAG TGCATCCACCAGGGCCACTGGTGTCCCAGCCAGGTTC AGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCG TCAGCAGCCTTCAGTCTGAAGATTTTGCAGTTTATTAC TGTCAGCAGTATGATAACTGGCCTCCGTACACTTTTGG CCAGGGGACCAAGGTGGAAATCAAA 285 4554 858 EIVMTQSPVTLSVSPGERATLSCRASQSVNSNLAWYQKK PGQAPRLLIYSASTRATGVPARFSGSGSGTEFTLTVSSLQ SEDFAVYYCQQYDNWPPYTFGQGTKVEIK 285 4555 859 RASQSVNSNLA 285 4556 860 AGGGCCAGTCAGAGTGTTAACAGCAACTTAGCC 285 4557 861 SASTRAT 285 4558 862 AGTGCATCCACCAGGGCCACT 285 4559 863 QQYDNWPPYT 285 4560 864 CAGCAGTATGATAACTGGCCTCCGTACACT 286 4561 865 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGA GGCCTTCACAGACCCTGTCCCTCACCTGCTCCGCCTCT GGTGCAGCCATCAATAGTGGTGATTATTACTGGAGTT GGATCCGCCAGGCCCCTGGGAGGGGCCTAGAGTGGAT TGGGTCCATTTCCAACCGTGGGGTCACCGACTACAAC CCGTCCCTCAAGAGTCGAGTTATCATATCAGCGGACA CGTCCAAGAATCAGTTCTCCCTGAGGCTGACCTCTGTG ACTGCCACAGACACGGCCGTGTATTATTGTGCCAGAG ATTTGGGTACTTTGGCCTTTGATCCCTACTACTATTAC GGTATTGACGTCTGGGGCCAAGGGACCACGGTCACCG TCTCCTCA 286 4562 866 QVQLQESGPGLVRPSQTLSLTCSASGAAINSGDYYWSWI RQAPGRGLEWIGSISNRGVTDYNPSLKSRVIISADTSKNQ FSLRLTSVTATDTAVYYCARDLGTLAFDPYYYYGIDVW GQGTTVTVSS 286 4563 867 AAINSGDYYWS 286 4564 868 GCAGCCATCAATAGTGGTGATTATTACTGGAGT 286 4565 869 SISNRGVTDYNPSLKS 286 4566 870 TCCATTTCCAACCGTGGGGTCACCGACTACAACCCGT CCCTCAAGAGT 286 4567 871 ARDLGTLAFDPYYYYGIDV 286 4568 872 GCCAGAGATTTGGGTACTTTGGCCTTTGATCCCTACTA CTATTACGGTATTGACGTC 286 4569 873 GACATCCGGATGACCCAGTCTCCAGCCACCCTGTCTTT GTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC AGTCAGAGTGTTAGCAGGCATTTAGCCTGGTACCAAC AAAAACCTGGCCAGGCTCCCCGGCTCCTCATCTATGA TGCATCATACAGGGTCACTGGCGTCCCAGACAGGTTC AGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCA TCAGCAGCCTGGAGTCTGAAGATTTTGCAATTTATTTC TGTCAGCAGCGTAGCACCTGGCCGACGTTCGGCCAAG GGACCAAGGTGGAAATCAAA 286 4570 874 DIRMTQSPATLSLSPGERATLSCRASQSVSRHLAWYQQK PGQAPRLLIYDASYRVTGVPDRFSGSGSGTDFTLTISSLES EDFAIYFCQQRSTWPTFGQGTKVEIK 286 4571 875 RASQSVSRHLA 286 4572 876 AGGGCCAGTCAGAGTGTTAGCAGGCATTTAGCC 286 4573 877 DASYRVT 286 4574 878 GATGCATCATACAGGGTCACT 286 4575 879 QQRSTWPT 286 4576 880 CAGCAGCGTAGCACCTGGCCGACG 287 4577 881 CAGGTGCAGCTGGTGGAATCTGGGGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTTGCCTGCACGGCGTC TGGATACGCCTTCACCAATTACAACATCCACTGGGTG CGACTGGCCCCTGGACAGGGACTTGAGTGGATGGCAA TTATCAACCCCGGTAGTGGTGGCACAGACTACTCAGA GAAGTTCCAGGGCAGGCTCACCTTGACCAGTGACACG TCCACGAGCACGGTGTACATGACGCTGGGCAGCCTGA GATATGAAGACACGGCCTTTTATTACTGTGCGAGAAG GGGTTACCCTGATTCGGGGAGTTACCCCCTTGACTACT GGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 287 4578 882 QVQLVESGAEVKKPGASVKVACTASGYAFTNYNIHWV RLAPGQGLEWMAIINPGSGGTDYSEKFQGRLTLTSDTST STVYMTLGSLRYEDTAFYYCARRGYPDSGSYPLDYWGQ GTLVTVSS 287 4579 883 YAFTNYNIH 287 4580 884 TACGCCTTCACCAATTACAACATCCAC 287 4581 885 IINPGSGGTDYSEKFQG 287 4582 886 ATTATCAACCCCGGTAGTGGTGGCACAGACTACTCAG AGAAGTTCCAGGGC 287 4583 887 ARRGYPDSGSYPLDY 287 4584 888 GCGAGAAGGGGTTACCCTGATTCGGGGAGTTACCCCC TTGACTAC 287 4585 889 GATATTGTGATGACGCAGTCTCCATCCTCCCTGTCTGC ATCTCTGGGAGACAGAGTCACCATCACTTGCCGGGCA GGTCGGAGCATTGCCACTTACTTAAATTGGTATCAGC AGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGG TGCATCCAGTTTGCAAAGTGGCGTCCCATCAAGGTTC AGTGGCAGTGGCTCTGGGACACATTTCACTCTCACCA TCAGCAGTCTGCAACCTGAGGATTTTGCAACTTACTAC TGTCAACAGAGTTACATCCGCCCTATCACTTTCGGCGG AGGGACCAAGGTGGAGATCAAA 287 4586 890 DIVMTQSPSSLSASLGDRVTITCRAGRSIATYLNWYQQK PGKAPKLLIYGASSLQSGVPSRFSGSGSGTHFTLTISSLQP EDFATYYCQQSYIRPITFGGGTKVEIK 287 4587 891 RAGRSIATYLN 287 4588 892 CGGGCAGGTCGGAGCATTGCCACTTACTTAAAT 287 4589 893 GASSLQS 287 4590 894 GGTGCATCCAGTTTGCAAAGT 287 4591 895 QQSYIRPIT 287 4592 896 CAACAGAGTTACATCCGCCCTATCACT 288 4593 897 CAGGTGCAGCTGCAGGAGTCCGGCCCAGGACTGGTGA AGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCT GGTCGTCTCCTCAGCAGTGGTGATTACTACTGGAGTTG GATCCGCCAGTCCCCAGGGAGGGGCCTGGAGTGGATT GGCTACGTCTATCACAGTGGGACCACCTCGTACAACC CGTCCCTCAAGAGTCGAATTACCATGACAGTGGACAC GTCCAAGAACCAGTTCAACCTGAGGTTGACCTCTGTA ACGGCCGCAGACACGGCCGTGTATTACTGTGCCAGAG ATCTCGGATATAGCAGTTCCTCTCCCGCCTTTTATTAC GGTATAGACTTCTGGGGCCCAGGGACCATGGTCACCG TCTCTTCA 288 4594 898 QVQLQESGPGLVKPSQTLSLTCTVSGRLLSSGDYYWSWI RQSPGRGLEWIGYVYHSGTTSYNPSLKSRITMTVDTSKN QFNLRLTSVTAADTAVYYCARDLGYSSSSPAFYYGIDFW GPGTMVTVSS 288 4595 899 RLLSSGDYYWS 288 4596 900 CGTCTCCTCAGCAGTGGTGATTACTACTGGAGT 288 4597 901 YVYHSGTTSYNPSLKS 288 4598 902 TACGTCTATCACAGTGGGACCACCTCGTACAACCCGT CCCTCAAGAGT 288 4599 903 ARDLGYSSSSPAFYYGIDF 288 4600 904 GCCAGAGATCTCGGATATAGCAGTTCCTCTCCCGCCTT TTATTACGGTATAGACTTC 288 4601 905 GAAATTGTATTGACACAGTCTCCAGCCACCCTGTCTTT GTCTCCAGGGCAAAGAGCGACCCTCTCCTGCAGGGCC AGTCAGAGTGTTGGCAACTACTTAGCCTGGTACCAAC AAAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGA TGCATCCAACAGGGTCACTGGCATCCCAGCCAGGTTC AGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCA TCAGCAGGCTAGAGTCTGAAGATTTTGCAGTTTATTAC TGTCAGCAGCGTAGCAACGGGGTCCTCACTTTCGGCG GAGGGACCAAAGTGGATATCAAA 288 4602 906 EIVLTQSPATLSLSPGQRATLSCRASQSVGNYLAWYQQK PGQAPRLLIYDASNRVTGIPARFSGSGSGTDFTLTISRLES EDFAVYYCQQRSNGVLTFGGGTKVDIK 288 4603 907 RASQSVGNYLA 288 4604 908 AGGGCCAGTCAGAGTGTTGGCAACTACTTAGCC 288 4605 909 DASNRVT 288 4606 910 GATGCATCCAACAGGGTCACT 288 4607 911 QQRSNGVLT 288 4608 912 CAGCAGCGTAGCAACGGGGTCCTCACT 289 4609 913 GAGGTGCAGCTGTTGGAGTCTGGGGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAGGGTCTCCTGCAAGGCTTC TGGATACACCTTCACCGACTACTTTATGAACTGGGTGC GACAGGCCCCTGGAGGGGGCCTTGAGTGGATGGGGTG GGTCAATCCTCTCAGTGGAGCCACAAAATATGCACAG AAGTTTCAGGGCAGGGTCACCATGACCACGGACACGT CCATCACCACAGGGTACCTGGACTTGAGGAGCCTGAG AGTTGACGACACGGCCATCTATTTTTGTGCGAGCCAG TCTTCCCCTTACACCCCGGGCGCTATGGGCGTCTGGGG CCAAGGGACCACGGTCACCGTCTCTTCA 289 4610 914 EVQLLESGAEVKKPGASVRVSCKASGYTFTDYFMNWV RQAPGGGLEWMGWVNPLSGATKYAQKFQGRVTMTTD TSITTGYLDLRSLRVDDTAIYFCASQSSPYTPGAMGVWG QGTTVTVSS 289 4611 915 YTFTDYFMN 289 4612 916 TACACCTTCACCGACTACTTTATGAAC 289 4613 917 WVNPLSGATKYAQKFQG 289 4614 918 TGGGTCAATCCTCTCAGTGGAGCCACAAAATATGCAC AGAAGTTTCAGGGC 289 4615 919 ASQSSPYTPGAMGV 289 4616 920 GCGAGCCAGTCTTCCCCTTACACCCCGGGCGCTATGG GCGTC 289 4617 921 GACATCCAGGTGACCCAGTCTCCATCCTCCCTGTCTGC CTCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCA AGTCAGAGCATTAGCGGCTATTTAAGTTGGTATCAGC AGAAACCAGGGAAAGCCCCTAACCTCCTGATCTATGC TACATCCAATTTATACAGTGGGGTCCCATCAAGGTTC AGTGGCCGTGATTCTGGGACAGATTTCACTCTCACCAT CACCAGTCTGCAACCTGAAGATTTTGCAACTTACTTCT GTCAACTGAATTCCGGTGCCCTATTCACTTTCGGCCCT GGGACCAAGGTGGAGATCAAA 289 4618 922 DIQVTQSPSSLSASVGDRVTITCRASQSISGYLSWYQQKP GKAPNLLIYATSNLYSGVPSRFSGRDSGTDFTLTITSLQPE DFATYFCQLNSGALFTFGPGTKVEIK 289 4619 923 RASQSISGYLS 289 4620 924 CGGGCAAGTCAGAGCATTAGCGGCTATTTAAGT 289 4621 925 ATSNLYS 289 4622 926 GCTACATCCAATTTATACAGT 289 4623 927 QLNSGALFT 289 4624 928 CAACTGAATTCCGGTGCCCTATTCACT 290 4625 929 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGA AGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCT GGTCCCTCCATCAGCGCTGGAGATTACAACTGGAATT GGATCCGCCAGGCCCCAGGGAAGGGCCTGGAGTGGG TTGGATACATCGATTACAGGGGCCTCACCCACTACAA CCCGTCCCTCAAGGGTCGACTTTCCATATTAATGGACA GGTCGGCGAACCAGTTCTCCCTGGAGCTGAATTCTGT GACTGCCGCAGACACGGCCGTCTACTACTGTGCCAGG GACGTGGGGGTCTATAGTGGCTACGATGTCTTTCACT ACTACGGCATGGACGTCTGGGGCCAGGGGACCACGGT CACCGTCTCCTCA 290 4626 930 QVQLQESGPGLVKPSQTLSLTCTVSGPSISAGDYNWNWI RQAPGKGLEWVGYIDYRGLTHYNPSLKGRLSILMDRSA NQFSLELNSVTAADTAVYYCARDVGVYSGYDVFHYYG MDVWGQGTTVTVSS 290 4627 931 PSISAGDYNWN 290 4628 932 CCCTCCATCAGCGCTGGAGATTACAACTGGAAT 290 4629 933 YIDYRGLTHYNPSLKG 290 4630 934 TACATCGATTACAGGGGCCTCACCCACTACAACCCGT CCCTCAAGGGT 290 4631 935 ARDVGVYSGYDVFHYYGMDV 290 4632 936 GCCAGGGACGTGGGGGTCTATAGTGGCTACGATGTCT TTCACTACTACGGCATGGACGTC 290 4633 937 GAAACGACACTCACGCAGTCTCCAGTCACCCTGTCTTT GTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC AGTCAGTATGTTAGGAACAACTACTTAGCCTGGTACC AACACAAACCTGGCCAGGCTCCCAGGCTCCTCATCTA TAGTGCTTCCAGCAGGGTCACTGGCACCCCAGACAGG TTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCA CCATCAGCAGACTGGAGCCTGAAGACTTTGCAGTGTA TTACTGTCAGCAGTATGGTGGCTCACCTCCGGTCACTT TCGGCCCTGGGACCAAAGTGGATATCAAA 290 4634 938 ETTLTQSPVTLSLSPGERATLSCRASQYVRNNYLAWYQH KPGQAPRLLIYSASSRVTGTPDRFSGSGSGTDFTLTISRLE PEDFAVYYCQQYGGSPPVTFGPGTKVDIK 290 4635 939 RASQYVRNNYLA 290 4636 940 AGGGCCAGTCAGTATGTTAGGAACAACTACTTAGCC 290 4637 941 SASSRVT 290 4638 942 AGTGCTTCCAGCAGGGTCACT 290 4639 943 QQYGGSPPVT 290 4640 944 CAGCAGTATGGTGGCTCACCTCCGGTCACT 291 4641 945 GAGGTGCAGCTGTTGGAGTCCGGGGGAGGCTTAGTTC AGCCTGGGGGGTCCCTGAGACTATCCTGTGCAGCCTC TGGATTCACCTTCAGTAATTACTGGATGCACTGGGTCC GCCAAGCTCCAGGGAAGGGGCTGGTGTGGGTCTCACG TATTAGCGGTGATGGAAGTGACACAACCTACGCGGAC TCCGTGGAGGGCCGATTCACCATCTCCAGAGACAACG CCAGGAGTACACTGTATCTTCAACTGAATAGTCTCAC AGGCGACGACACGGCTGTGTATTATTGTGCAAGAGAT TTGTGGACCACCTCGCCCTACTTTGACCTCTGGGGCCA GGGAACCCTGGTCACCGTCTCCTCA 291 4642 946 EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYWMHWVR QAPGKGLVWVSRISGDGSDTTYADSVEGRFTISRDNARS TLYLQLNSLTGDDTAVYYCARDLWTTSPYFDLWGQGTL VTVSS 291 4643 947 FTFSNYWMH 291 4644 948 TTCACCTTCAGTAATTACTGGATGCAC 291 4645 949 RISGDGSDTTYADSVEG 291 4646 950 CGTATTAGCGGTGATGGAAGTGACACAACCTACGCGG ACTCCGTGGAGGGC 291 4647 951 ARDLWTTSPYFDL 291 4648 952 GCAAGAGATTTGTGGACCACCTCGCCCTACTTTGACCT C 291 4649 953 GAAATTGTATTGACACAGTCTCCTGGCACCCTGTCTGC ATCTATTGGAGACAGAGTCACCATCACTTGCCGGGCC AGTCAGAGTCTTAATGGCTGGTTGGCCTGGTATCAGC AGAAACCAGGGAAAGCCCCTAGGCTCCTCATCTATAA GTCGTCTAGTTTAGAAAGCGGGGTCCCATCAAGGTTC AGCGGCAGTGCATCTGGGACAGAATTCACTCTCACCA TCAGCAGCCTGCAGCCTGACGATTTTGCAACTTATTAC TGCCAACAGTATAATAGTTGGGCGTTCGGCCAAGGGA CCAAGGTGGACGTCAAA 291 4650 954 EIVLTQSPGTLSASIGDRVTITCRASQSLNGWLAWYQQK PGKAPRLLIYKSSSLESGVPSRFSGSASGTEFTLTISSLQPD DFATYYCQQYNSWAFGQGTKVDVK 291 4651 955 RASQSLNGWLA 291 4652 956 CGGGCCAGTCAGAGTCTTAATGGCTGGTTGGCC 291 4653 957 KSSSLES 291 4654 958 AAGTCGTCTAGTTTAGAAAGC 291 4655 959 QQYNSWA 291 4656 960 CAACAGTATAATAGTTGGGCG 292 4657 961 CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGA AGCCTTCGGAGACCCTGTCCCTCACCTGCGCTGTCTAT GGTGGGTCCTTCAGTGGTTACTCCTGGAGCTGGATCC GCCAGTCCCCAGGGAAGGGGCTGGAGTGGATTGGAG AAATCAATCATAGAGGAAGCACCAACTACAACCCGTC CCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCG AAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCG CCGCGGACACGGCTGTGTACTACTGTGCGGGGACCAA TTATGGAGAGGTTAATACGAGTAACCAATACTTCTTC GGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCG TCTCCTCA 292 4658 962 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYSWSWIR QSPGKGLEWIGEINHRGSTNYNPSLKSRVTISVDTSKNQF SLKLSSVTAADTAVYYCAGTNYGEVNTSNQYFFGMDV WGQGTTVTVSS 292 4659 963 GSFSGYSWS 292 4660 964 GGGTCCTTCAGTGGTTACTCCTGGAGC 292 4661 965 EINHRGSTNYNPSLKS 292 4662 966 GAAATCAATCATAGAGGAAGCACCAACTACAACCCGT CCCTCAAGAGT 292 4663 967 AGTNYGEVNTSNQYFFGMDV 292 4664 968 GCGGGGACCAATTATGGAGAGGTTAATACGAGTAACC AATACTTCTTCGGTATGGACGTC 292 4665 969 GACATCCGGTTGACCCAGTCTCCATCCTCCCTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCA AGTCAGAGCATTACCACCTATTTAAATTGGTATCAGC AGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATGC TGCATCCAATTTGGAAAGTGGGGTCCCATCAAGTTTC AGTGGCAGTGGATTTGGGACAGACTTCACTCTCACCA TCAGCAGTCTGCAACCTGACGATTTTGCAACTTACTAC TGTCAACAGAGTTACAGTGCCCCGCTCACCTTCGGCG GAGGGACCAAAGTGGATATCAAA 292 4666 970 DIRLTQSPSSLSASVGDRVTITCRASQSITTYLNWYQQKP GKAPKLLIYAASNLESGVPSSFSGSGFGTDFTLTISSLQPD DFATYYCQQSYSAPLTFGGGTKVDIK 292 4667 971 RASQSITTYLN 292 4668 972 CGGGCAAGTCAGAGCATTACCACCTATTTAAAT 292 4669 973 AASNLES 292 4670 974 GCTGCATCCAATTTGGAAAGT 292 4671 975 QQSYSAPLT 292 4672 976 CAACAGAGTTACAGTGCCCCGCTCACC 293 4673 977 CAGGTCCAGCTGGTACAGTCTGGGGCTGGGGTGAAGA AGCCTGGGGCCTCAGTGAGGGTCTCATGCACGGCCTC TGGATACACCTTCACCGACTACTTTATAAACTGGGTGC GACAGGCCCCTGGAGGGGGCCTTGAGTGGATGGGGTG GGTCAATCCTCTCAGTGGAGCCACAAGATACGCCCAG AACTTTGCGGGCAGGGTCACCATGACCACGGACACGT CCATCACCACAGGATATCTGGACTTACGGAACCTGCG ACTTGACGACACGGCCGTCTATTTTTGTGCGAGCCAGT CTTCACCTTACACGCCGGGCGCTATGGACGTCTGGGG CCAAGGGACCACGGTCACCGTCTCCTCA 293 4674 978 QVQLVQSGAGVKKPGASVRVSCTASGYTFTDYFINWVR QAPGGGLEWMGWVNPLSGATRYAQNFAGRVTMTTDTS ITTGYLDLRNLRLDDTAVYFCASQSSPYTPGAMDVWGQ GTTVTVSS 293 4675 979 YTFTDYFIN 293 4676 980 TACACCTTCACCGACTACTTTATAAAC 293 4677 981 WVNPLSGATRYAQNFAG 293 4678 982 TGGGTCAATCCTCTCAGTGGAGCCACAAGATACGCCC AGAACTTTGCGGGC 293 4679 983 ASQSSPYTPGAMDV 293 4680 984 GCGAGCCAGTCTTCACCTTACACGCCGGGCGCTATGG ACGTC 293 4681 985 GATATTGTGATGACCCAGTCTCCATCCTCCCTGTCTGC ATCTGTAGGAGACAGAGTCTCCATCACTTGCCGGACA AGTCAGACCATTAGTGGCTATATAAGTTGGTATCAGA AGAAACCAGGAAAAGCCCCTAAACTCCTGATCTATGC TGCATCAAATATGTACAGTGGGGTCCCATCAAGGTTC AGTGGCAGTGAATCTGGGACAGATTTCACTCTCACCA TCACCAGTCTGCAACCTGAAGATTTTGCAACTTACTTC TGTCAACTGAATTCCGGTGCCCTATTCACTTTCGGCCC TGGGACCAAAGTGGATATCAAA 293 4682 986 DIVMTQSPSSLSASVGDRVSITCRTSQTISGYISWYQKKP GKAPKLLIYAASNMYSGVPSRFSGSESGTDFTLTITSLQP EDFATYFCQLNSGALFTFGPGTKVDIK 293 4683 987 RTSQTISGYIS 293 4684 988 CGGACAAGTCAGACCATTAGTGGCTATATAAGT 293 4685 989 AASNMYS 293 4686 990 GCTGCATCAAATATGTACAGT 293 4687 991 QLNSGALFT 293 4688 992 CAACTGAATTCCGGTGCCCTATTCACT 294 4689 993 GAGGTGCAGCTGGTGGAGTCTGCAGCAGAGGTGAAA AAGCCCGGGGAGTCTCTGAAGATCTCCTGTAAGGGTT CTGGATACAGTTTTGCCAGCCACTGGATCGGTTGGGT CCGCCAAATGCCCGGGAAAGGCCTGGAGTTGATGGGA TTCATCTATCCTGGTGACTCTGATACCAGATACAACCC GTCCTTCCAAGGCCAGGTCACCATCTCAGCCGACAAG TCCATCAGCACCGCCTACCTGCAGTGGACCAGGCTGA AGGCCTCGGACACCGCCATGTACTACTGTGGCCAGGC AGTGGCGGGGGGTGAATATTTCCACCACTGGGGCCAG GGCACCCTGGTCACCGTCTCCTCA 294 4690 994 EVQLVESAAEVKKPGESLKISCKGSGYSFASHWIGWVR QMPGKGLELMGFIYPGDSDTRYNPSFQGQVTISADKSIST AYLQWTRLKASDTAMYYCGQAVAGGEYFHHWGQGTL VTVSS 294 4691 995 YSFASHWIG 294 4692 996 TACAGTTTTGCCAGCCACTGGATCGGT 294 4693 997 FIYPGDSDTRYNPSFQG 294 4694 998 TTCATCTATCCTGGTGACTCTGATACCAGATACAACCC GTCCTTCCAAGGC 294 4695 999 GQAVAGGEYFHH 294 4696 1000 GGCCAGGCAGTGGCGGGGGGTGAATATTTCCACCAC 294 4697 1001 GATATTGTGATGACGCAGTCTCCAGCCACCCTGTCTGT GTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC AGTCAGAGTCTTGGCAGCGACTTAGCCTGGTACCAGC AGAAACCTGGCCAGACTCCCAGGCTCCTCATCTATGA TGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTC AGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCA TCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTAC TGTCAGCACTATAATAATTGGCCCCGGGGGTTCGGCC AAGGGACCAAGGTGGAAATCAAA 294 4698 1002 DIVMTQSPATLSVSPGERATLSCRASQSLGSDLAWYQQK PGQTPRLLIYDASTRATGIPARFSGSGSGTEFTLTISSLQSE DFAVYYCQHYNNWPRGFGQGTKVEIK 294 4699 1003 RASQSLGSDLA 294 4700 1004 AGGGCCAGTCAGAGTCTTGGCAGCGACTTAGCC 294 4701 1005 DASTRAT 294 4702 1006 GATGCATCCACCAGGGCCACT 294 4703 1007 QHYNNWPRG 294 4704 1008 CAGCACTATAATAATTGGCCCCGGGGG 295 4705 1009 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACGGGTG AAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTC TGGTGTCTCCGTCACCATTAATGATTACTACTGGACTT GGCTCCGCCAGTCCCCAGGGAAAGGCCTGGAGTGGAT TGGAAACATCTATAACAGTGGGAGCACCTACCAGAAC CCGTCCCTCCAGAGTCGAGTTACCATGTCAGTGGACA CGGCCAAGAACCACTTCTCCCTGAAGCTGACCTCTGT CACTGCCGCAGATACGGCCGTCTATTACTGTGCCAGA GATTTAGGCACTGCCAACAACTACTACTTCGGTATGG ACGTCTGGGGCCTAGGGACCACGGTCACCGTCTCCTC A 295 4706 1010 QVQLQESGPGRVKPSQTLSLTCTVSGVSVTINDYYWTW LRQSPGKGLEWIGNIYNSGSTYQNPSLQSRVTMSVDTAK NHFSLKLTSVTAADTAVYYCARDLGTANNYYFGMDVW GLGTTVTVSS 295 4707 1011 VSVTINDYYWT 295 4708 1012 GTCTCCGTCACCATTAATGATTACTACTGGACT 295 4709 1013 NIYNSGSTYQNPSLQS 295 4710 1014 AACATCTATAACAGTGGGAGCACCTACCAGAACCCGT CCCTCCAGAGT 295 4711 1015 ARDLGTANNYYFGMDV 295 4712 1016 GCCAGAGATTTAGGCACTGCCAACAACTACTACTTCG GTATGGACGTC 295 4713 1017 GAAATTGTGATGACGCAGTCTCCAGCCACCCTGTCTTT GTCTCCAGGGGAAAGAGCCACTCTCTCCTGCAGGGCC AGTCAGAGTGTTAGCACCTACTTAGCCTGGTACCAAC AGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATAA TGGATCCAACAGGGTCACTGGCACCCCAGCCAGGTTC AGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCA TCAGCAGCGTAGAGCCTGAAGATTTTGCAGTTTATTA CTGTCAGCAGCGTAGCAACTGGCCTCCGTACACTTTTG GCCAGGGGACCAAGGTGGAGATCAAA 295 4714 1018 EIVMTQSPATLSLSPGERATLSCRASQSVSTYLAWYQQK PGQAPRLLIYNGSNRVTGTPARFSGSGSGTDFTLTISSVEP EDFAVYYCQQRSNWPPYTFGQGTKVEIK 295 4715 1019 RASQSVSTYLA 295 4716 1020 AGGGCCAGTCAGAGTGTTAGCACCTACTTAGCC 295 4717 1021 NGSNRVT 295 4718 1022 AATGGATCCAACAGGGTCACT 295 4719 1023 QQRSNWPPYT 295 4720 1024 CAGCAGCGTAGCAACTGGCCTCCGTACACT 296 4721 1025 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGA AGCCTTCGGAGACCCTGTCCCTCACCTGCTCGGTCTCT GGTGCCTCCGTCACCAGTAGGGAATACTACTGGGGCT GGATCCGCCAGGCCCCCGGGAAGGGTCTGCAGTGGAT TGCCAGCATTCATCACAGTCCTTTTCAAAGTGACGGC AACCCGTCCCTGACGAGTCGCGTCTCCAGTTCCGTAGT CACGTCCAAGAACCAGTTGGCCCTGAGGCTGAGCTCT GTGACCGCCGCAGACACGGCTGTATATTACTGTGCGG GCGCGTTTTGGGAGGTTTGGACTGGCCTTTATTCACCG CCGTTTGACTTTTGGGGCCAGGGAATCCTGGTCACCGT CTCCTCA 296 4722 1026 QVQLQESGPGLVKPSETLSLTCSVSGASVTSREYYWGWI RQAPGKGLQWIASIHHSPFQSDGNPSLTSRVSSSVVTSKN QLALRLSSVTAADTAVYYCAGAFWEVWTGLYSPPFDF WGQGILVTVSS 296 4723 1027 ASVTSREYYWG 296 4724 1028 GCCTCCGTCACCAGTAGGGAATACTACTGGGGC 296 4725 1029 SIHHSPFQSDGNPSLTS 296 4726 1030 AGCATTCATCACAGTCCTTTTCAAAGTGACGGCAACC CGTCCCTGACGAGT 296 4727 1031 AGAFWEVWTGLYSPPFDF 296 4728 1032 GCGGGCGCGTTTTGGGAGGTTTGGACTGGCCTTTATTC ACCGCCGTTTGACTTT 296 4729 1033 GAAATTGTAATGACACAGTCTCCAGGGACCCTGTCTT TGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCTGGGC CAGTCAGACTGTTAGCAGCGGCTACTTAGCCTGGTAC CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCT ATGGTGCATCTACCAGGGCCACTGACATCCCAGACAG GTTCAGTGGCAGTGGGTCTGGGACAGGCTTCACTCTC ACCATCAGCAGACTGGAGCCTGAAGATCTTGCAGTCT ATTACTGTCAGCAGTATAGCAGTTCACCACTCACTTTC GGCGGCGGGACCAAGGTGGAAATCAAA 296 4730 1034 EIVMTQSPGTLSLSPGERATLSCWASQTVSSGYLAWYQQ KPGQAPRLLIYGASTRATDIPDRFSGSGSGTGFTLTISRLE PEDLAVYYCQQYSSSPLTFGGGTKVEIK 296 4731 1035 WASQTVSSGYLA 296 4732 1036 TGGGCCAGTCAGACTGTTAGCAGCGGCTACTTAGCC 296 4733 1037 GASTRAT 296 4734 1038 GGTGCATCTACCAGGGCCACT 296 4735 1039 QQYSSSPLT 296 4736 1040 CAGCAGTATAGCAGTTCACCACTCACT 297 4737 1041 CAGGTGCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCTCGTGCAAGACTTC TGGTTACACCTTTTCCAACTACGGTATCAGCTGGCTGC GACAGGCCCCTGGACAAGGGCTTGAGTGGATGGCATG GATCAGCCCTTATAATGGGAACACAAAGTCTGCACAG AGGTTTCAGGGCAGAGTCATCATGACCACAGACACAT CCACGAGGACAGCCCACATGGAGGTGAAGAGCCTGA GAACTGACGACACGGCCACATATTACTGTGCGAGAGA TCCAGCAGTCGATGCAATACCGATGCTTGACTACTGG GGCCAGGGAACCACGGTCACCGTCTCCTCA 297 4738 1042 QVQLVQSGAEVKKPGASVKVSCKTSGYTFSNYGISWLR QAPGQGLEWMAWISPYNGNTKSAQRFQGRVIMTTDTST RTAHMEVKSLRTDDTATYYCARDPAVDAIPMLDYWGQ GTTVTVSS 297 4739 1043 YTFSNYGIS 297 4740 1044 TACACCTTTTCCAACTACGGTATCAGC 297 4741 1045 WISPYNGNTKSAQRFQG 297 4742 1046 TGGATCAGCCCTTATAATGGGAACACAAAGTCTGCAC AGAGGTTTCAGGGC 297 4743 1047 ARDPAVDAIPMLDY 297 4744 1048 GCGAGAGATCCAGCAGTCGATGCAATACCGATGCTTG ACTAC 297 4745 1049 GACATCCAGGTGACCCAGTCTCCACTCTCCCTGCCCGT CACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTA GTCAAAGCCTCGTGTACACTGATGGAAACACCTACTT GAGCTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGG CGCCTAATTTATAGGGTTTCTCACCGGGACTCTGGGGT CCCAGACAGATTCACCGGCAGTGGGTCAGGCACTGAT TTCACACTGATAATCCGCAGGGTGGAGGCTGAGGATG TTGGGGTTTATTACTGCATGCAAGGTACACACTGGCCT CTCACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA 297 4746 1050 DIQVTQSPLSLPVTLGQPASISCRSSQSLVYTDGNTYLSW FQQRPGQSPRRLIYRVSHRDSGVPDRFTGSGSGTDFTLIIR RVEAEDVGVYYCMQGTHWPLTFGGGTKVEIK 297 4747 1051 RSSQSLVYTDGNTYLS 297 4748 1052 AGGTCTAGTCAAAGCCTCGTGTACACTGATGGAAACA CCTACTTGAGC 297 4749 1053 RVSHRDS 297 4750 1054 AGGGTTTCTCACCGGGACTCT 297 4751 1055 MQGTHWPLT 297 4752 1056 ATGCAAGGTACACACTGGCCTCTCACT 298 4753 1057 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCGTGGTCC AGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTC TGGATTCACGTTCAGTGACTATGCCATGCACTGGGTCC GCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAA TCATATCATATGATGCAAATAATAAATATTATGCAGA CTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAAT TCCAAGAACACGGTGTATCTGCAAATGAACAGCCTGA GACCTGAGGACACGGCTGTATATTACTGTGCGAAAGA AGAGTGGCTGGTGCCAGCCTACTGGGGCCAGGGAATC CTGGTCACCGTCTCCTCA 298 4754 1058 QVQLVQSGGGVVQPGRSLRLSCAASGFTFSDYAMHWV RQAPGKGLEWVAIISYDANNKYYADSVKGRFTISRDNS KNTVYLQMNSLRPEDTAVYYCAKEEWLVPAYWGQGIL VTVSS 298 4755 1059 FTFSDYAMH 298 4756 1060 TTCACGTTCAGTGACTATGCCATGCAC 298 4757 1061 IISYDANNKYYADSVKG 298 4758 1062 ATCATATCATATGATGCAAATAATAAATATTATGCAG ACTCCGTGAAGGGC 298 4759 1063 AKEEWLVPAY 298 4760 1064 GCGAAAGAAGAGTGGCTGGTGCCAGCCTAC 298 4761 1065 CAGTCTGTGCTGACTCAGCCTGCCTCCGTGTCTGGGTC TCCTGGACAGTCGATCACCATCTCCTGCACTGGAACC AGCAGTGACGTTGGTGGATATAATTACGTCTCCTGGT ACCAACAACACCCAGGCAAAGCCCCCAAACTCTTAAT TTATGAGGTCTCTAATCGGCCCTCAGGGGTTTCTAATC GCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTG ACCATCTCTGGGCTCCAGCCTGAGGACGAGGCTGATT ATTACTGCAGCTCATATTCAACCAATAGTGCCCCCTTT GGAACTGGGACCAAGCTCACCGTCCTA 298 4762 1066 QSVLTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQ QHPGKAPKLLIYEVSNRPSGVSNRFSGSKSGNTASLTISG LQPEDEADYYCSSYSTNSAPFGTGTKLTVL 298 4763 1067 TGTSSDVGGYNYVS 298 4764 1068 ACTGGAACCAGCAGTGACGTTGGTGGATATAATTACG TCTCC 298 4765 1069 EVSNRPS 298 4766 1070 GAGGTCTCTAATCGGCCCTCA 298 4767 1071 SSYSTNSAP 298 4768 1072 AGCTCATATTCAACCAATAGTGCCCCC 299 4769 1073 CAGGTCCAGCTTGTGCAGTCTGGGGGAGGCGTGGTCC AGTCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTC TGGATTCACCTTCAGTGACAATGGCATGCACTGGGTC CGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCA GGAATCTTTCATGATGGGAGTAATAAACAATATGCAG AATCCGTGAAGGGCCGATTCATCATCTCCAGAGACAA TTCCAAGAACACTCTCTATCTGCAAATGAACAGCCTG AGAGCCGAGGACACGGCTCTATATTTCTGTGCGAGAG CCCCTTACGATATTTGGAGCGGATATTGTCTTGACTAC TGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 299 4770 1074 QVQLVQSGGGVVQSGRSLRLSCAASGFTFSDNGMHWV RQAPGKGLEWVAGIFHDGSNKQYAESVKGRFIISRDNSK NTLYLQMNSLRAEDTALYFCARAPYDIWSGYCLDYWG QGTLVTVSS 299 4771 1075 FTFSDNGMH 299 4772 1076 TTCACCTTCAGTGACAATGGCATGCAC 299 4773 1077 GIFHDGSNKQYAESVKG 299 4774 1078 GGAATCTTTCATGATGGGAGTAATAAACAATATGCAG AATCCGTGAAGGGC 299 4775 1079 ARAPYDIWSGYCLDY 299 4776 1080 GCGAGAGCCCCTTACGATATTTGGAGCGGATATTGTC TTGACTAC 299 4777 1081 GACATCCGGATGACCCAGTCTCCAGCCACCCTGTCTCT GTCTCCAGGGGAAAGCGCCACCCTCTCCTGCAGGGCC AGTCAGAGTGTTATCAACAACTTAGCCTGGTACCAGC AGAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGG TGCATCTACCAGGGCCACTGGTATCCCAGCCAGGTTC AGTGGCAGTGGGTCTGAGACAGAGTTCACTCTCACTA TCAGCAGCCTGCAGTCTGAAGATTTCGCGGTTTATCAC TGTCAGCAGTATAGTATCTGGCCTCAGACTTTTGGCCA GGGGACCAAGCTGGAGATCAAA 299 4778 1082 DIRMTQSPATLSLSPGESATLSCRASQSVINNLAWYQQR PGQAPRLLIYGASTRATGIPARFSGSGSETEFTLTISSLQSE DFAVYHCQQYSIWPQTFGQGTKLEIK 299 4779 1083 RASQSVINNLA 299 4780 1084 AGGGCCAGTCAGAGTGTTATCAACAACTTAGCC 299 4781 1085 GASTRAT 299 4782 1086 GGTGCATCTACCAGGGCCACT 299 4783 1087 QQYSIWPQT 299 4784 1088 CAGCAGTATAGTATCTGGCCTCAGACT 300 4785 1089 GAGGTGCAGCTGTTGGAGTCCGGGGGAGGCGTGGTCC AGTCTGGGAGGTCCCTGAGACTCTCCTGTGTAGCGTCT GGATTCACCTTCAGTGACAGTGGCATGCACTGGGTCC GCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAG GTTTATTTTATGATGGAAGTAATAAACAATATGCAGA CTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAAT TCCAAGAGCACACTGTATCTGCAGATGAACAGCCTGA GGGCCGAGGACACGGCTGTTTATTACTGTGCGAGAGC CCCTTACGATATTTGGAGTGGTTATTGTCTTGACTACT GGGGCCAGGGAACCCTGGTCACTGTCTCCTCA 300 4786 1090 EVQLLESGGGVVQSGRSLRLSCVASGFTFSDSGMHWVR QAPGKGLEWVAGLFYDGSNKQYADSVKGRFTISRDNSK STLYLQMNSLRAEDTAVYYCARAPYDIWSGYCLDYWG QGTLVTVSS 300 4787 1091 FTFSDSGMH 300 4788 1092 TTCACCTTCAGTGACAGTGGCATGCAC 300 4789 1093 GLFYDGSNKQYADSVKG 300 4790 1094 GGTTTATTTTATGATGGAAGTAATAAACAATATGCAG ACTCCGTGAAGGGC 300 4791 1095 ARAPYDIWSGYCLDY 300 4792 1096 GCGAGAGCCCCTTACGATATTTGGAGTGGTTATTGTCT TGACTAC 300 4793 1097 GAAATTGTATTGACACAGTCTCCAGCCACCCTGTATAT GTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC AGTCAGAGTGTTAACAACAACTTAGCCTGGTACCAGC AGAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGG TGCATCTACCAGGGCCACTGGTATCCCAGCCAGGTTC AGTGGCAGTGGGTCTGAGACAGAGTTCACTCTCACTA TCAGCAGCCTGCAGTCTGAAGATTTTGCGGTTTATCAC TGTCAGCAGTATAGTATCTGGCCTCAGACTTTTGGCCA GGGGACCAAGCTGGAGATCAAA 300 4794 1098 EIVLTQSPATLYMSPGERATLSCRASQSVNNNLAWYQQ RPGQAPRLLIYGASTRATGIPARFSGSGSETEFTLTISSLQ SEDFAVYHCQQYSIWPQTFGQGTKLEIK 300 4795 1099 RASQSVNNNLA 300 4796 1100 AGGGCCAGTCAGAGTGTTAACAACAACTTAGCC 300 4797 1101 GASTRAT 300 4798 1102 GGTGCATCTACCAGGGCCACT 300 4799 1103 QQYSIWPQT 300 4800 1104 CAGCAGTATAGTATCTGGCCTCAGACT 301 4801 1105 CAGGTCCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCTCGTGCAAGACTTC TGGTTACACCTTTTCCAACTACGGTATCAGCTGGCTGC GACAGGCCCCTGGACAAGGGCTTGAGTGGATGGCATG GATCAGCCCTTATAATGGGAACACAAAGTCTGCACAG AGGTTTCAGGGCAGAGTCATCATGACCACAGACACAT CCACGAGGACAGCCCACATGGAGGTGAAGAGCCTGA GAACTGACGACACGGCCACATATTACTGTGCGAGAGA TCCAGCAGTCGATGCAATACCGATGCTTGACTACTGG GGCCAGGGAACCATGGTCACCGTCTCCTCA 301 4802 1106 QVQLVQSGAEVKKPGASVKVSCKTSGYTFSNYGISWLR QAPGQGLEWMAWISPYNGNTKSAQRFQGRVIMTTDTST RTAHMEVKSLRTDDTATYYCARDPAVDAIPMLDYWGQ GTMVTVSS 301 4803 1107 YTFSNYGIS 301 4804 1108 TACACCTTTTCCAACTACGGTATCAGC 301 4805 1109 WISPYNGNTKSAQRFQG 301 4806 1110 TGGATCAGCCCTTATAATGGGAACACAAAGTCTGCAC AGAGGTTTCAGGGC 301 4807 1111 ARDPAVDAIPMLDY 301 4808 1112 GCGAGAGATCCAGCAGTCGATGCAATACCGATGCTTG ACTAC 301 4809 1113 GAAATTGTGTTGACACAGTCTCCACTCTCCCTGCCCGT CACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTA GTCAAAGCCTCGTGTACACTGATGGAAACACCTACTT GAGCTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGG CGCCTAATTTATAGGGTTTCTCACCGGGACTCTGGGGT CCCAGACAGATTCACCGGCAGTGGGTCAGGCACTGAT TTCACACTGATAATCCGCAGGGTGGAGGCTGAGGATG TTGGGGTTTATTACTGCATGCAAGGTACACACTGGCCT CTCACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA 301 4810 1114 EIVLTQSPLSLPVTLGQPASISCRSSQSLVYTDGNTYLSW FQQRPGQSPRRLIYRVSHRDSGVPDRFTGSGSGTDFTLIIR RVEAEDVGVYYCMQGTHWPLTFGGGTKVEIK 301 4811 1115 RSSQSLVYTDGNTYLS 301 4812 1116 AGGTCTAGTCAAAGCCTCGTGTACACTGATGGAAACA CCTACTTGAGC 301 4813 1117 RVSHRDS 301 4814 1118 AGGGTTTCTCACCGGGACTCT 301 4815 1119 MQGTHWPLT 301 4816 1120 ATGCAAGGTACACACTGGCCTCTCACT 302 4817 1121 GAGGTGCAGCTGGTGGAGTCGGGCCCAAGACTGGTGA GGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCT GGAGGCTTCATCAAAACTAGTAGTTACTACTGGGGCT GGATCCGTCAGCCCCCAGGGAAGGGGCTAGAGTGGAT TGGGAGTATCTATTATGCTGGGACCACCTACTACAAC CCGTCCCTCCAGAGTCGAGTCACCATGTCCGTTGACA CGTCGAACAACCAGTTCTCCCTGAAGCTGAACTCTGT GACCGCCGCAGACACGGCTGTATATTACTGTGCGACC GCCTGGACTTTTGACCACTGGGGCCAGGGAACCCTGG TCACTGTCTCCTCA 302 4818 1122 EVQLVESGPRLVRPSETLSLTCTVSGGFIKTSSYYWGWIR QPPGKGLEWIGSIYYAGTTYYNPSLQSRVTMSVDTSNNQ FSLKLNSVTAADTAVYYCATAWTFDHWGQGTLVTVSS 302 4819 1123 GFIKTSSYYWG 302 4820 1124 GGCTTCATCAAAACTAGTAGTTACTACTGGGGC 302 4821 1125 SIYYAGTTYYNPSLQS 302 4822 1126 AGTATCTATTATGCTGGGACCACCTACTACAACCCGTC CCTCCAGAGT 302 4823 1127 ATAWTFDH 302 4824 1128 GCGACCGCCTGGACTTTTGACCAC 302 4825 1129 GAAATTGTATTGACACAGTCTCCAGCCACCCTGTCCTT GTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC AGTCAGAGTCTTAGCAACTACTTAGCCTGGTACCAAC AGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGA TGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTC AGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCA TCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTAC TGTCAGCTGCGTGGCCACTGGCCCCCCACGATCACCTT CGGCCAAGGGACACGACTGGAGATTAAA 302 4826 1130 EIVLTQSPATLSLSPGERATLSCRASQSLSNYLAWYQQKP GQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPE DFAVYYCQLRGHWPPTITFGQGTRLEIK 302 4827 1131 RASQSLSNYLA 302 4828 1132 AGGGCCAGTCAGAGTCTTAGCAACTACTTAGCC 302 4829 1133 DASNRAT 302 4830 1134 GATGCATCCAACAGGGCCACT 302 4831 1135 QLRGHWPPTIT 302 4832 1136 CAGCTGCGTGGCCACTGGCCCCCCACGATCACC 303 4833 107 CAGGTCCAGCTTGTACAGTCTGGGGGAGGCTTGGTTC AGCCGGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTC TGGATTCGCCTTTAGCGACTATACCATGAGCTGGGTCC GCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAA GTGTTAGTGGCACGGGTGGTACCTCATACTACGCAGA CTCCGTGAATGGCCGGTTCGCCATCTCCAGAGAGAAT TCCAAGAACACGCTGTTTCTGCAAATGGACAGCCTGA GAGCCGAGGACACGGCCACTTACTACTGTGCCAAAGA TGGGTTGAGGGACGTATCGAGGGTTTATTACATCGAC GTCTGGGGCAAAGGGACCACGGTCACCGTCTCCTCA 303 4834 1138 QVQLVQSGGGLVQPGGSLRLSCAASGFAFSDYTMSWVR QAPGKGLEWVSSVSGTGGTSYYADSVNGRFAISRENSK NTLFLQMDSLRAEDTATYYCAKDGLRDVSRVYYIDVW GKGTTVTVSS 303 4835 1139 FAFSDYTMS 303 4836 1140 TTCGCCTTTAGCGACTATACCATGAGC 303 4837 1141 SVSGTGGTSYYADSVNG 303 4838 1142 AGTGTTAGTGGCACGGGTGGTACCTCATACTACGCAG ACTCCGTGAATGGC 303 4839 1143 AKDGLRDVSRVYYIDV 303 4840 1144 GCCAAAGATGGGTTGAGGGACGTATCGAGGGTTTATT ACATCGACGTC 303 4841 1145 CAGCCTGTGCTGACTCAGCCTGCCTCCGTGTCTGGGTC TCCTGGACAGTCGATCACCATCTCCTGCACTGGAACC AGCCGTGACATTGGTTCTCATGACTCTGTCTCCTGGTA CCAACAAAAGCCAGGCAAAGCCCCCAAACTCATCATT TATGCAGTCAGAAATCGGCCCTCAGGGCTTTCTAATC GCTTCTCTGGTTCCAAGTCTGGCAACACGGCCTCCCTG ACCATCTCTGGGCTCCAGACTGAAGACGAAGGTGACT ATTACTGCAGCTCATATAGAAACGGCAACGCTCTGGG GGTCTTCGGAACTGGGACCAAGGTCACCGTCCTC 303 4842 1146 QPVLTQPASVSGSPGQSITISCTGTSRDIGSHDSVSWYQQ KPGKAPKLIIYAVRNRPSGLSNRFSGSKSGNTASLTISGL QTEDEGDYYCSSYRNGNALGVFGTGTKVTVL 303 4843 1147 TGTSRDIGSHDSVS 303 4844 1148 ACTGGAACCAGCCGTGACATTGGTTCTCATGACTCTGT CTCC 303 4845 1149 AVRNRPS 303 4846 1150 GCAGTCAGAAATCGGCCCTCA 303 4847 1151 SSYRNGNALGV 303 4848 1152 AGCTCATATAGAAACGGCAACGCTCTGGGGGTC 304 4849 1153 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTTC AGCCGGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTC TGGATTCGCCTTTAGCAACTATGCCATGAGCTGGGTCC GCCAGGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAAG TGTTAGTGGCACGGGTGGTACCACATACTACGCAGAC TCCGTGAACGGGCGGTTCGCCATCTCCAGAGAGAATT CCAGGAACACCCTCTATCTGCAAATGGATAGCCTGAG AGTCGAGGACACGGCCACTTATTACTGTGCCAAAGAT GGGTTGAGGGACTTATCGAGGGTCTATTACATCGACG TCTGGGGCAAAGGGGCCACGGTCACCGTCTCTTCA 304 4850 1154 QVQLVESGGGLVQPGGSLRLSCAASGFAFSNYAMSWVR QAPGKGLEWVSSVSGTGGTTYYADSVNGRFAISRENSR NTLYLQMDSLRVEDTATYYCAKDGLRDLSRVYYIDVW GKGATVTVSS 304 4851 1155 FAFSNYAMS 304 4852 1156 TTCGCCTTTAGCAACTATGCCATGAGC 304 4853 1157 SVSGTGGTTYYADSVNG 304 4854 1158 AGTGTTAGTGGCACGGGTGGTACCACATACTACGCAG ACTCCGTGAACGGG 304 4855 1159 AKDGLRDLSRVYYIDV 304 4856 1160 GCCAAAGATGGGTTGAGGGACTTATCGAGGGTCTATT ACATCGACGTC 304 4857 1161 CAGTCTGTCCTGACTCAGCCTGCCTCCGTGTCTGGGTC TCCTGGACAGTCGATCACCATCTCCTGCACTGGAACC AGCCGTGACATTGGTAGTCATGACTATGTCTCCTGGTA CCAACAACACCCAGGCAAAGCCCCCAAACTCATCATT TATGGGGTCAATAATCGGCCCTCAGGACTTTCTAATC GCTTCTCTGGTTCCAAGTCTGGCAACACGGCCTCCCTG ACCATCTCTGGGCTCCAGACTGAAGACGAAGGTGACT ATTACTGCAGCTCATATAGAAACGGCAACACTCTGGG GGTCTTCGGAACTGGGACCAAGCTCACCGTCCTA 304 4858 1162 QSVLTQPASVSGSPGQSITISCTGTSRDIGSHDYVSWYQQ HPGKAPKLIIYGVNNRPSGLSNRFSGSKSGNTASLTISGL QTEDEGDYYCSSYRNGNTLGVFGTGTKLTVL 304 4859 1163 TGTSRDIGSHDYVS 304 4860 1164 ACTGGAACCAGCCGTGACATTGGTAGTCATGACTATG TCTCC 304 4861 1165 GVNNRPS 304 4862 1166 GGGGTCAATAATCGGCCCTCA 304 4863 1167 SSYRNGNTLGV 304 4864 1168 AGCTCATATAGAAACGGCAACACTCTGGGGGTC 305 4865 1169 CAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGA AGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCCTC TGGAGGCACCTTCAGCGGCTACGCTATCAACTGGGTG CGACAGGCCCCTGGACAAGGGCTCGAGTGGATGGGA GGGATCATCCATATATTTGGGACAGTAAACTACGCTC CGAAGTTCCAGGGCAGACTCACGATAACCGCGGACGC ATCCACGGGCACAGCCTACATGGAATTGAGCAGCCTG ATGTCTGAGGACACGGCCCTATATTATTGTGCGAGAG ATGCTTACGAAGTGTGGACCGGTTCTTATCTCCCCCCT TTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCT CCTCA 305 4866 1170 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSGYAINWVR QAPGQGLEWMGGIIHIFGTVNYAPKFQGRLTITADASTG TAYMELSSLMSEDTALYYCARDAYEVWTGSYLPPFDY WGQGTLVTVSS 305 4867 1171 GTFSGYAIN 305 4868 1172 GGCACCTTCAGCGGCTACGCTATCAAC 305 4869 1173 GIIHIFGTVNYAPKFQG 305 4870 1174 GGGATCATCCATATATTTGGGACAGTAAACTACGCTC CGAAGTTCCAGGGC 305 4871 1175 ARDAYEVWTGSYLPPFDY 305 4872 1176 GCGAGAGATGCTTACGAAGTGTGGACCGGTTCTTATC TCCCCCCTTTTGACTAC 305 4873 1177 GAAACGACACTCACGCAGTCTCCAGGCACCCTGTCTT TGTCTCCCGGGGAAAGAGTCACCCTCTCCTGCAGGGC CAGTCAGACTGTTACAAGCAACTACTTAGCCTGGTAC CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCT ATGATGCATTCACCAGGGCCACTGGCGTCCCAGCCAG GTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTC ACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTTT ACTATTGTCAGCAGTATGGTAGCTCATTCCTCACTTTC GGCGGAGGGACCAAGGTGGAAATCAAA 305 4874 1178 ETTLTQSPGTLSLSPGERVTLSCRASQTVTSNYLAWYQQ KPGQAPRLLIYDAFTRATGVPARFSGSGSGTDFTLTISRL EPEDFAVYYCQQYGSSFLTFGGGTKVEIK 305 4875 1179 RASQTVTSNYLA 305 4876 1180 AGGGCCAGTCAGACTGTTACAAGCAACTACTTAGCC 305 4877 1181 DAFTRAT 305 4878 1182 GATGCATTCACCAGGGCCACT 305 4879 1183 QQYGSSFLT 305 4880 1184 CAGCAGTATGGTAGCTCATTCCTCACT 306 4881 1185 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCC AGTCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCATC TGGATTCATCTTCAGTGACAATGGCATGCACTGGGTC CGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCA GGTATTTTTTATGATGGAAGTAATAAACAATATGCAG ACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAA TTCCAAGAACACACTGTATCTGCAAATGAAGAGCCTG AGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAG CCCCTTACGATATCTGGAGTGGTTATTGTCTTGACTAC TGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 306 4882 1186 EVQLVESGGGVVQSGRSLRLSCAASGFIFSDNGMHWVR QAPGKGLEWVAGIFYDGSNKQYADSVKGRFTISRDNSK NTLYLQMKSLRAEDTAVYYCARAPYDIWSGYCLDYWG QGTLVTVSS 306 4883 1187 FIFSDNGMH 306 4884 1188 TTCATCTTCAGTGACAATGGCATGCAC 306 4885 1189 GIFYDGSNKQYADSVKG 306 4886 1190 GGTATTTTTTATGATGGAAGTAATAAACAATATGCAG ACTCCGTGAAGGGC 306 4887 1191 ARAPYDIWSGYCLDY 306 4888 1192 GCGAGAGCCCCTTACGATATCTGGAGTGGTTATTGTCT TGACTAC 306 4889 1193 GACATCCAGGTGACCCAGTCTCCAGCCACCCTGTCTA TGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGC CAGTCAGAGTGTTAACAACAACTTAGCCTGGTACCAG CAGAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATG GTGCATCTACGAGGGCCACTGGTATCCCAGCCAGGTT CAGTGGCAGTGGGTCTGAGACAGAGTTCACTCTCACT ATCAGCAGCCTGCAGTCTGAAGATTTTGCGGTTTATCA CTGTCAGCAGTATAGTATCTGGCCTCAGACTTTTGGCC AGGGGACCAAGGTGGAAATCAAA 306 4890 1194 DIQVTQSPATLSMSPGERATLSCRASQSVNNNLAWYQQ RPGQAPRLLIYGASTRATGIPARFSGSGSETEFTLTISSLQ SEDFAVYHCQQYSIWPQTFGQGTKVEIK 306 4891 1195 RASQSVNNNLA 306 4892 1196 AGGGCCAGTCAGAGTGTTAACAACAACTTAGCC 306 4893 1197 GASTRAT 306 4894 1198 GGTGCATCTACGAGGGCCACT 306 4895 1199 QQYSIWPQT 306 4896 1200 CAGCAGTATAGTATCTGGCCTCAGACT 307 4897 1201 CAGGTCCAGCTTGTACAGTCTGGGGCTGAACTAAAGA AGCCTGGCTCCTCGGTGAAAGTCTCCTGCAAGGCTTCT GCAGACACCTTCAAAAGTTATGCTATCAACTGGGTGC GGCAGGCCCCTGGACAAGGACTTGAGTGGATGGGAG AGTTCATCCCAATCTTTGGTGTCTCACCCTCCGCACAG AAGTTCCAGGGCAGAGTCACCATTACCGCGGACAGAT CCACGTCCACAGCCTACATGGAGTTGAGCAGCCTGAA ATCTGATGACTCGGCCATTTATTACTGTGCGACACGTC TGTATACGTTGGGGTCCCCTTTTGACAATTGGGGCCAG GGGACCACGGTCACCGTCTCCTCA 307 4898 1202 QVQLVQSGAELKKPGSSVKVSCKASADTFKSYAINWVR QAPGQGLEWMGEFIPIFGVSPSAQKFQGRVTITADRSTST AYMELSSLKSDDSAIYYCATRLYTLGSPFDNWGQGTTV TVSS 307 4899 1203 DTFKSYAIN 307 4900 1204 GACACCTTCAAAAGTTATGCTATCAAC 307 4901 1205 EFIPIFGVSPSAQKFQG 307 4902 1206 GAGTTCATCCCAATCTTTGGTGTCTCACCCTCCGCACA GAAGTTCCAGGGC 307 4903 1207 ATRLYTLGSPFDN 307 4904 1208 GCGACACGTCTGTATACGTTGGGGTCCCCTTTTGACAA T 307 4905 1209 CAGCCTGTGCTGACTCAGCCTCGCTCAGTGTCCGGGTC TCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACC AGTAGTGATGTTGGTGATTATGACTATGTCTCCTGGTA CCAACACCTCCCAGGCGAAGTCCCCAAACTCATAGTT TATAATGTCATTAAGCGGCCCTCTGGGGTCCCTGATCG CTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGA CCATCTCTGGGCTCCAGGCTGAGGATGAGGCTGACTA TTACTGCTGCTCATATGCAGGCAGGTATATTTATGTCT TCGGCAGTGGGACCAAGCTCACCGTCCTA 307 4906 1210 QPVLTQPRSVSGSPGQSVTISCTGTSSDVGDYDYVSWYQ HLPGEVPKLIVYNVIKRPSGVPDRFSGSKSGNTASLTISG LQAEDEADYYCCSYAGRYIYVFGSGTKLTVL 307 4907 1211 TGTSSDVGDYDYVS 307 4908 1212 ACTGGAACCAGTAGTGATGTTGGTGATTATGACTATG TCTCC 307 4909 1213 NVIKRPS 307 4910 1214 AATGTCATTAAGCGGCCCTCT 307 4911 1215 CSYAGRYIYV 307 4912 1216 TGCTCATATGCAGGCAGGTATATTTATGTC 308 4913 1217 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCCTGGTCA AGCCTGGGGAGTCCCTGAGACTCTCCTGTGCAGCCTC TGGATTCACCCTTAGTGGCTACTACATGAATTGGGTCC GCCAGGCTCCAGGGAGGGGGCTGGAGTGGGTCTCCTC CATTAGTGGTGGTAGTAATTACATAAACTACGCCGAC TCAGTGAAGGGCCGGTTCACCATCTCCAGAGACAACG CCAAGAACTCACTCTATCTGCAAATGAACAGCCTGAG AGTCGAGGACACGGCTGTCTATTACTGTGCGAGGGTC CACGTGGATTTAGTGACTACGATTTTTGGGGTTGACTT TGACTTCTGGGGCCAGGGAACCCTGGTCACTGTCTCCT CA 308 4914 1218 EVQLLESGGGLVKPGESLRLSCAASGFTLSGYYMNWVR QAPGRGLEWVSSISGGSNYINYADSVKGRFTISRDNAKN SLYLQMNSLRVEDTAVYYCARVHVDLVTTIFGVDFDFW GQGTLVTVSS 308 4915 1219 FTLSGYYMN 308 4916 1220 TTCACCCTTAGTGGCTACTACATGAAT 308 4917 1221 SISGGSNYINYADSVKG 308 4918 1222 TCCATTAGTGGTGGTAGTAATTACATAAACTACGCCG ACTCAGTGAAGGGC 308 4919 1223 ARVHVDLVTTIFGVDFDF 308 4920 1224 GCGAGGGTCCACGTGGATTTAGTGACTACGATTTTTG GGGTTGACTTTGACTTC 308 4921 1225 CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGG CCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAG CAGCTCCAACATCGGGGCAGGGTATGATGTACACTGG TACCAGCAACTTCCAGGAACAGCCCCCAAACTCCTCA TCTATGGTAACACCAATCGGCCCGCAGGGGTCCCTGA CCGATTCTCTGGCTCCAAGTCTGGCTCCTCAGCCTCCC TGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGA TTATTACTGCCAGTCGTATGACAGCAGCCTGAGTGGT GCGATCTTCGGCGGAGGGACCAAGCTCACCGTCCTA 308 4922 1226 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKLLIYGNTNRPAGVPDRFSGSKSGSSASLAITG LQAEDEADYYCQSYDSSLSGAIFGGGTKLTVL 308 4923 1227 TGSSSNIGAGYDVH 308 4924 1228 ACTGGGAGCAGCTCCAACATCGGGGCAGGGTATGATG TACAC 308 4925 1229 GNTNRPA 308 4926 1230 GGTAACACCAATCGGCCCGCA 308 4927 1231 QSYDSSLSGAI 308 4928 1232 CAGTCGTATGACAGCAGCCTGAGTGGTGCGATC 309 4929 1233 CAGGTGCAGCTGCAGGAGTCCGGAGCTGAGGTGAAG ATGCGTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTT CTGGTTACACCTTTAGTCACTATGGTATCAGTTGGGTG CGACAGGCCCCTGGACAAGGGCTCGAGTGGATGGGAT TTATCAGCGCTTACAATCATAACACAAAGTATGCACA GACCGTCCAGGGCAGAGTCACCTTGAGCACAGACACA TCCACGAGCACAGCCTACATGGAGCTGAGGAGCCTGA GACCTGACGACACGGCCATGTATTACTGTGCGAGAGA ACCCCCGAGTGACGATGCTGCAAGGCTCTTTGACTAC TGGGGCCAGGGAACCCTGGTCACTGTCTCCTCA 309 4930 1234 QVQLQESGAEVKMRGASVKVSCKASGYTFSHYGISWVR QAPGQGLEWMGFISAYNHNTKYAQTVQGRVTLSTDTST STAYMELRSLRPDDTAMYYCAREPPSDDAARLFDYWG QGTLVTVSS 309 4931 1235 YTFSHYGIS 309 4932 1236 TACACCTTTAGTCACTATGGTATCAGT 309 4933 1237 FISAYNHNTKYAQTVQG 309 4934 1238 TTTATCAGCGCTTACAATCATAACACAAAGTATGCAC AGACCGTCCAGGGC 309 4935 1239 AREPPSDDAARLFDY 309 4936 1240 GCGAGAGAACCCCCGAGTGACGATGCTGCAAGGCTCT TTGACTAC 309 4937 1241 GAAACGACACTCACGCAGTCTCCACGCTCCCTGCCCG TCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCT AGTCAAAGCCTCGTGTACAGTGAAGGAAACACCTACT TGAGTTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAG GCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGG GTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTG ATTTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGA TGTTGGGGTTTATTATTGCATGCAAGGTACACAGTGG CCTGTGACATTCGGCCAAGGGACCAAGGTGGAAATCA AA 309 4938 1242 ETTLTQSPRSLPVTLGQPASISCRSSQSLVYSEGNTYLSW FQQRPGQSPRRLIYKVSNRDSGVPDRFSGSGSGTDFTLKI SRVEAEDVGVYYCMQGTQWPVTFGQGTKVEIK 309 4939 1243 RSSQSLVYSEGNTYLS 309 4940 1244 AGGTCTAGTCAAAGCCTCGTGTACAGTGAAGGAAACA CCTACTTGAGT 309 4941 1245 KVSNRDS 309 4942 1246 AAGGTTTCTAACCGGGACTCT 309 4943 1247 MQGTQWPVT 309 4944 1248 ATGCAAGGTACACAGTGGCCTGTGACA 310 4945 1249 CAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAGGGTCTCCTGCAAGGTTTA CGGTCACACCCTCAGTGAATTATCCATGCACTGGGTG CGACAGGGTCCTGAAGGAGGCCTTGAGTGGATGGGA GCTTTTGATCATGAAGATGGTGAAGGAATCTACCCAC AGAAGTTCCAGGGCAGAATCACCATGACCGCGGACAT ATCGACAGACACAGCCCACATGGAACTGAGGAGCCTC AGATCTGAGGACACGGCCGTTTATTACTGTGCAACAC CGACCCCGGTTGGAGCAACGGACTTCTGGGGCCAGGG AACCCTGGTCACCGTCTCCTCA 310 4946 1250 QVQLVQSGAEVKKPGASVRVSCKVYGHTLSELSMHWV RQGPEGGLEWMGAFDHEDGEGIYPQKFQGRITMTADIS TDTAHMELRSLRSEDTAVYYCATPTPVGATDFWGQGTL VTVSS 310 4947 1251 HTLSELSMH 310 4948 1252 CACACCCTCAGTGAATTATCCATGCAC 310 4949 1253 AFDHEDGEGIYPQKFQG 310 4950 1254 GCTTTTGATCATGAAGATGGTGAAGGAATCTACCCAC AGAAGTTCCAGGGC 310 4951 1255 ATPTPVGATDF 310 4952 1256 GCAACACCGACCCCGGTTGGAGCAACGGACTTC 310 4953 1257 GACATCCGGGTGACCCAGTCTCCATCCTCCCTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCA AGTCAGAGCATTAGCAGCTACTTAAATTGGTATCAAC AGAAACCAGGAAAAGCCCCTAAGCTCCTGATCTATGC TGCATCCACTTTGCAGAGGGGGGGCCCATCAAGATTC AGTGGCAGTGGATCTGGGACAGATTTCACTCTCAGCA TCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTAT TGTCAACAGACTTACATTATTCCATACACTTTTGGCCA GGGGACCAAGCTGGAGATCAAA 310 4954 1258 DIRVTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKP GKAPKLLIYAASTLQRGGPSRFSGSGSGTDFTLSISSLQPE DFATYYCQQTYIIPYTFGQGTKLEIK 310 4955 1259 RASQSISSYLN 310 4956 1260 CGGGCAAGTCAGAGCATTAGCAGCTACTTAAAT 310 4957 1261 AASTLQR 310 4958 1262 GCTGCATCCACTTTGCAGAGG 310 4959 1263 QQTYIIPYT 310 4960 1264 CAACAGACTTACATTATTCCATACACT 311 4961 1265 CAGGTGCAGCTGCAGGAGTCGGGCCCGGGACTGGTGA AGCCTTCGGAGACCCTGTCCCTCACCTGCAGTGTCTCT GGTGGCTCCATCACCAATGTTAATTACTACTGGGGCT GGATCCGCCAGCCCCCCGGGAAGGGCCTGGAGTGGAT TGGGAGTATCTATTATAATGGAAACACCTACTACAAC CCGTCCCTCCAGAGTCGAGTCACCATGTCCGTGGACA CGTCCAAGAACCACTTCTCCCTGAGGCTGACGTCTGT GACCGCCGCAGACACGGCTGTATATTTTTGTGCGAGA GAGGGGCCTAATTGGGAATTGTTGAATGCTTTCGATA TCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 311 4962 1266 QVQLQESGPGLVKPSETLSLTCSVSGGSITNVNYYWGWI RQPPGKGLEWIGSIYYNGNTYYNPSLQSRVTMSVDTSKN HFSLRLTSVTAADTAVYFCAREGPNWELLNAFDIWGQG TTVTVSS 311 4963 1267 GSITNVNYYWG 311 4964 1268 GGCTCCATCACCAATGTTAATTACTACTGGGGC 311 4965 1269 SIYYNGNTYYNPSLQS 311 4966 1270 AGTATCTATTATAATGGAAACACCTACTACAACCCGT CCCTCCAGAGT 311 4967 1271 AREGPNWELLNAFDI 311 4968 1272 GCGAGAGAGGGGCCTAATTGGGAATTGTTGAATGCTT TCGATATC 311 4969 1273 GACATCCAGGTGACCCAGCCACCCTCGGTGTCAGTGG CCCCAGGACAGACGGCCAGGATTACCTGTGGGGGAA ACAACATTGGAAGTAAAAATGTGCACTGGTACCAGCA GAAGCCAGGCCGGGCCCCTGTCTTGGTCGTCTATGAG GATACCCACCGGCCCTCAGGGATCCCTGAGCGATTCT CTGGCTCCAACTCTGGGAACACGGCCACCCTGACCAT CAGTAGGGTCGAAGCCGGGGATGAGGCCGACTATTAC TGTCAGGTGTGGGATACTAGTAGTGATCATGTGGTAT TCGGCGGAGGGACCAAGCTCACCGTCCTA 311 4970 1274 DIQVTQPPSVSVAPGQTARITCGGNNIGSKNVHWYQQKP GRAPVLVVYEDTHRPSGIPERFSGSNSGNTATLTISRVEA GDEADYYCQVWDTSSDHVVFGGGTKLTVL 311 4971 1275 GGNNIGSKNVH 311 4972 1276 GGGGGAAACAACATTGGAAGTAAAAATGTGCAC 311 4973 1277 EDTHRPS 311 4974 1278 GAGGATACCCACCGGCCCTCA 311 4975 1279 QVWDTSSDHVV 311 4976 1280 CAGGTGTGGGATACTAGTAGTGATCATGTGGTA 312 4977 1281 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCCTGGTCA AGCCTGAGGGGTCCCTGAGACTCTCCTGTGCAGCCTC TGGATTCACCTTCAGTAGCTATAGCATGAACTGGGTC CGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTAGTAGTAGTAGTAGTTACATATACTACGCAGA CTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAAC GCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGA GAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGT CTCAACAGAATTGGGCTACTACTACATGGACGTCTGG GGCAAAGGGACCACGGTCACTGTCTCCTCA 312 4978 1282 QVQLVQSGGGLVKPEGSLRLSCAASGFTFSSYSMNWVR QAPGKGLEWVSSISSSSSYIYYADSVKGRFTISRDNAKNS LYLQMNSLRAEDTAVYYCARVSTELGYYYMDVWGKG TTVTVSS 312 4979 1283 FTFSSYSMN 312 4980 1284 TTCACCTTCAGTAGCTATAGCATGAAC 312 4981 1285 SISSSSSYIYYADSVKG 312 4982 1286 TCCATTAGTAGTAGTAGTAGTTACATATACTACGCAG ACTCAGTGAAGGGC 312 4983 1287 ARVSTELGYYYMDV 312 4984 1288 GCGAGAGTCTCAACAGAATTGGGCTACTACTACATGG ACGTC 312 4985 1289 CAGTCTGTCCTGACGCAGCCGCCCTCAGTGTCTGGGG CCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAG CAGCTCCAACATCGGGGCAGGTTATGATGTACACTGG TACCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTCA TCTATGGTAACAGCAATCGGCCCTCAGGGGTCCCTGA CCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCC TGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGA TTATTACTGCCAGTCCTATGACAGCAGCCTGAGTGTG GTATTCGGCGGAGGGACCAAGCTGACCGTCCTA 312 4986 1290 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSSLSVVFGGGTKLTVL 312 4987 1291 TGSSSNIGAGYDVH 312 4988 1292 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATG TACAC 312 4989 1293 GNSNRPS 312 4990 1294 GGTAACAGCAATCGGCCCTCA 312 4991 1295 QSYDSSLSVV 312 4992 1296 CAGTCCTATGACAGCAGCCTGAGTGTGGTA 313 4993 1297 CAGGTCCAGCTTGTACAGTCTGGGGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGATTTCCTGCAAGGCTTC GGGATACCCCTTCAGTTCCTATCCTATGCATTGGGTGC GCCAGGCCCCCGGACAAAGGCTTGAGTGGATGGGATG GATCAACGTTGACAATGAGAACACAAAATATTCATGG AAGTTCCGGGGCAGAGTCACCATTACCAGGGACACAT CCGCGAGCACAGTTTACATGGAGCTGAGCAGTCTGAT ATCTGAAGACACGGCTGTGTATTACTGTGGGAGAGAC TGGGACGGGGCGATCCGTGTCTTGGACTACTGGGGCC AGGGAACCCTGGTCACCGTCTCCTCA 313 4994 1298 QVQLVQSGAEVKKPGASVKISCKASGYPFSSYPMHWVR QAPGQRLEWMGWINVDNENTKYSWKFRGRVTITRDTS ASTVYMELSSLISEDTAVYYCGRDWDGAIRVLDYWGQG TLVTVSS 313 4995 1299 YPFSSYPMH 313 4996 1300 TACCCCTTCAGTTCCTATCCTATGCAT 313 4997 1301 WINVDNENTKYSWKFRG 313 4998 1302 TGGATCAACGTTGACAATGAGAACACAAAATATTCAT GGAAGTTCCGGGGC 313 4999 1303 GRDWDGAIRVLDY 313 5000 1304 GGGAGAGACTGGGACGGGGCGATCCGTGTCTTGGACT AC 313 5001 1305 GATATTGTGATGACTCAGACTCCAGACTCCCTGGCTGT GTCTCTGGGCGAGAGGGCCACCATCACCTGCAAGTCC AGCCAGAGTGTTTTATTCAGCTCCGACAATAAGAACT ACTTAGCTTGGTACCAGCAGAAACCGGGACAGCCTCC TAAATTGCTCATTTACTGGGCATCTATCCGGGAATCCG GGGTCCCTGACCGATTCGGTGGCAGCGGGTCTGGGAC ACATTTCACTCTCACCATCACCAGCGTGCAGGCTGCA GATGTGGCAGTTTATTACTGTCAGCAATATTATGGTAA TTTCCCCACCTTCGGCCAAGGGACACGACTGGAGATT AAA 313 5002 1306 DIVMTQTPDSLAVSLGERATITCKSSQSVLFSSDNKNYLA WYQQKPGQPPKLLIYWASIRESGVPDRFGGSGSGTHFTL TITSVQAADVAVYYCQQYYGNFPTFGQGTRLEIK 313 5003 1307 KSSQSVLFSSDNKNYLA 313 5004 008 AAGTCCAGCCAGAGTGTTTTATTCAGCTCCGACAATA AGAACTACTTAGCT 313 5005 1309 WASIRES 313 5006 1310 TGGGCATCTATCCGGGAATCC 313 5007 1311 QQYYGNFPT 313 5008 1312 CAGCAATATTATGGTAATTTCCCCACC 314 5009 1313 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCGTGGTCC AGCCTGGGAGGTCCCTGAGACTTTCCTGTGCAGCCTCT GGATTCACCTTCAGAAACTATGGCATGCACTGGGTCC GCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTAGCGG CTGCATCGTATGATGGGAGTAGTAAGTACTTTGCAGA CGCCGTGAAGGGCCGATTCAGCATCTCCAGAGACAAT ACCAAGAACACGCTGTCTCTGCAAATGACCAGCCTGA GAGCTGAGGACACGGCTGTGTATTACTGTGCAAGAGA CCCCGGAGTGGGAAGTTATTATAACGTGGTGGGTATG GACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCT CA 314 5010 1314 QVQLVQSGGGVVQPGRSLRLSCAASGFTFRNYGMHWV RQAPGKGLEWVAAASYDGSSKYFADAVKGRFSISRDNT KNTLSLQMTSLRAEDTAVYYCARDPGVGSYYNVVGMD VWGQGTTVTVSS 314 5011 1315 FTFRNYGMH 314 5012 1316 TTCACCTTCAGAAACTATGGCATGCAC 314 5013 1317 AASYDGSSKYFADAVKG 314 5014 1318 GCTGCATCGTATGATGGGAGTAGTAAGTACTTTGCAG ACGCCGTGAAGGGC 314 5015 1319 ARDPGVGSYYNVVGMDV 314 5016 1320 GCAAGAGACCCCGGAGTGGGAAGTTATTATAACGTGG TGGGTATGGACGTC 314 5017 1321 GACATCCGGTTGACCCAGTCTCCACTCTCCCTGCCCGT CACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTA GTCAAAGCCTCGTATACAGTGATGGAAACACCTACTT GAATTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGG CGCCTAATTTATAGGGTTTCTCACCGGGACTCTGGGGT CCCAGACAGATTCAGCGGCAGTGAGTCAGGCACTGAT TTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATG TTGGCGTTTATTACTGCATGCAAGGTACACACTGGCCT CCTACGTTCGGCCAAGGGACCAAGGTGGAGATCAAA 314 5018 1322 DIRLTQSPLSLPVTLGQPASISCRSSQSLVYSDGNTYLNW FQQRPGQSPRRLIYRVSHRDSGVPDRFSGSESGTDFTLKI SRVEAEDVGVYYCMQGTHWPPTFGQGTKVEIK 314 5019 1323 RSSQSLVYSDGNTYLN 314 5020 1324 AGGTCTAGTCAAAGCCTCGTATACAGTGATGGAAACA CCTACTTGAAT 314 5021 1325 RVSHRDS 314 5022 1326 AGGGTTTCTCACCGGGACTCT 314 5023 1327 MQGTHWPPT 314 5024 1328 ATGCAAGGTACACACTGGCCTCCTACG 315 5025 1329 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCGCCTGCAAGGTTTC CGGATCCAGCCTCACTGAATTGTCCATTCAATGGGTG CGCTTGCCTCCTGGCAAACGCCTTGAGTGGCTGGGAG CTTTTGATGCTGAAGATGGTGCACCAATCTACTCACCG AAATTCCAGGGCAGAGTCACCATGACCGAGGACAGAT CGACAGAGACAGCCTACATGGAGGTGACCAGCCTGA GATCTGAGGACACGGCCCTCTATTACTGTGCGACTCC CCTTCCCGCGGGAGCCCTTGACAAGTGGGGCCAGGGA ACCCTGGTCACCGTCTCCTCA 315 5026 1330 QVQLVQSGAEVKKPGASVKVACKVSGSSLTELSIQWVR LPPGKRLEWLGAFDAEDGAPIYSPKFQGRVTMTEDRSTE TAYMEVTSLRSEDTALYYCATPLPAGALDKWGQGTLVT VSS 315 5027 1331 SSLTELSIQ 315 5028 1332 TCCAGCCTCACTGAATTGTCCATTCAA 315 5029 1333 AFDAEDGAPIYSPKFQG 315 5030 1334 GCTTTTGATGCTGAAGATGGTGCACCAATCTACTCACC GAAATTCCAGGGC 315 5031 1335 ATPLPAGALDK 315 5032 1336 GCGACTCCCCTTCCCGCGGGAGCCCTTGACAAG 315 5033 1337 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC TTCCGTAGGAGACAGAGTCACCATCTCTTGCCGGGCA AGTCAGACTATAAGCAGATATTTAAATTGGTATCAGG TCAAGCCAGGGACAGCCCCTAAGCTCCTAATCTACGC TGCATCCAGTTTGCAAACTGGGGTCCCATCAAGATTC AGTGCCAGTGGATCTGGGGCAGATTTCACTCTCACCA TCAGCAGTCTGCAACCTGAAGATTTTGCGACTTACCA CTGTCAACAAACTTACATTATTCCGTACACTTTTGGCC AGGGGACCAAAGTGGATATCAAA 315 5034 1338 DIQMTQSPSSLSASVGDRVTISCRASQTISRYLNWYQVKP GTAPKLLIYAASSLQTGVPSRFSASGSGADFTLTISSLQPE DFATYHCQQTYIIPYTFGQGTKVDIK 315 5035 1339 RASQTISRYLN 315 5036 1340 CGGGCAAGTCAGACTATAAGCAGATATTTAAAT 315 5037 1341 AASSLQT 315 5038 1342 GCTGCATCCAGTTTGCAAACT 315 5039 1343 QQTYIIPYT 315 5040 1344 CAACAAACTTACATTATTCCGTACACT 316 5041 1345 GAGGTGCAGCTGGTGGAGTCGGGCCCAGGACTGGTGA AGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCT GATGTCCTCATCAGCAGTGGTGATTACTACTGGAGTT GGATCCGCCAGTCCCCAGGGAAGGGCCTGGAGTGGCT TGGGTACATCTATTATACCGGGAAGACCAAATATAAT CCGTCCCTCGAGAGTCGAATTACCATGTCAGTAGACA CGTCCAAGAACCAGTTCTCCCTGAGGTTGAGCTCTGTT ACTGCCGCAGACACGGCCGTATATTTCTGTACCAGAG ATCTGGGATATAGCACCTCGTCCCCCTCCTTTTACTAT GGGATGGACGTCTGGGGCCAAGGGACCACGGTCACC GTCTCCTCA 316 5042 1346 EVQLVESGPGLVKPSQTLSLTCTVSDVLISSGDYYWSWI RQSPGKGLEWLGYIYYTGKTKYNPSLESRITMSVDTSKN QFSLRLSSVTAADTAVYFCTRDLGYSTSSPSFYYGMDV WGQGTTVTVSS 316 5043 1347 VLISSGDYYWS 316 5044 1348 GTCCTCATCAGCAGTGGTGATTACTACTGGAGT 316 5045 1349 YIYYTGKTKYNPSLES 316 5046 1350 TACATCTATTATACCGGGAAGACCAAATATAATCCGT CCCTCGAGAGT 316 5047 1351 TRDLGYSTSSPSFYYGMDV 316 5048 1352 ACCAGAGATCTGGGATATAGCACCTCGTCCCCCTCCTT TTACTATGGGATGGACGTC 316 5049 1353 GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTT GTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC AGTCAGAGTGTTGGGACCTACTTAGCCTGGTACCAAC AGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGA TGCATCTTACAGGGTCACTGGCATCCCAGCCAGGTTC AGTGCCAGTGGGTCTGCGACAGACTTCACTCTCACCA TCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTTC TGTCAGCAGCGTACCAACTGGCCGATCACCTTCGGCC AGGGGACACGACTGGAGATTAAA 316 5050 1354 EIVLTQSPATLSLSPGERATLSCRASQSVGTYLAWYQQK PGQAPRLLIYDASYRVTGIPARFSASGSATDFTLTISSLEP EDFAVYFCQQRTNWPITFGQGTRLEIK 316 5051 1355 RASQSVGTYLA 316 5052 1356 AGGGCCAGTCAGAGTGTTGGGACCTACTTAGCC 316 5053 1357 DASYRVT 316 5054 1358 GATGCATCTTACAGGGTCACT 316 5055 1359 QQRTNWPIT 316 5056 1360 CAGCAGCGTACCAACTGGCCGATCACC 317 5057 1361 CAGGTCCAGCTTGTGCAGTCTGGACCTGAGGTGAAGA AGCCTGGGGCCTCAGTGACGGTCTCCTGCAAGGCTTC CGGTTACACCTTTAGCCATTACGGTATTAGTTGGGTGC GACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGGTG GATCAGCGCGTACCATGGTCAGACAAACTATGCACAG AACTTCCAGGGCAGAGTCACCATGACCACAGACACAT CCTCGAACACAGCCTACATGGAGGTCAGGAGCCTGAG ATCTGACGACACGGCCGTTTATTTCTGTGCGAGAGAT GTCTTTTCGAAAACAGCAGCTCGAATCTTTGACTACTG GGGCCAGGGAACCCTGGTCACCGTCTCCTCA 317 5058 1362 QVQLVQSGPEVKKPGASVTVSCKASGYTFSHYGISWVR QAPGQGLEWMGWISAYHGQTNYAQNFQGRVTMTTDTS SNTAYMEVRSLRSDDTAVYFCARDVFSKTAARIFDYWG QGTLVTVSS 317 5059 1363 YTFSHYGIS 317 5060 1364 TACACCTTTAGCCATTACGGTATTAGT 317 5061 1365 WISAYHGQTNYAQNFQG 317 5062 066 TGGATCAGCGCGTACCATGGTCAGACAAACTATGCAC AGAACTTCCAGGGC 317 5063 1367 ARDVFSKTAARIFDY 317 5064 1368 GCGAGAGATGTCTTTTCGAAAACAGCAGCTCGAATCT TTGACTAC 317 5065 1369 GAAATTGTATTGACGCAGTCTCCACTCTCCCTGCCCGT CACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTA GTCAAAGCCTCGAATATAGTGACGGAAACACCTACTT GAGTTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGG CGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGT CCCAGACAGATTCAGCGGCAGTCAGTCAGGCACTGAT TTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATG TTGGGGTTTATTACTGCATGCAAGCTACAGACTGGCC GGTCACGTTCGGCCAAGGGACCAAGCTGGAGATCAAA 317 5066 1370 EIVLTQSPLSLPVTLGQPASISCRSSQSLEYSDGNTYLSWF QQRPGQSPRRLIYKVSNRDSGVPDRFSGSQSGTDFTLKIS RVEAEDVGVYYCMQATDWPVTFGQGTKLEIK 317 5067 1371 RSSQSLEYSDGNTYLS 317 5068 1372 AGGTCTAGTCAAAGCCTCGAATATAGTGACGGAAACA CCTACTTGAGT 317 5069 1373 KVSNRDS 317 5070 1374 AAGGTTTCTAACCGGGACTCT 317 5071 1375 MQATDWPVT 317 5072 1376 ATGCAAGCTACAGACTGGCCGGTCACG 318 5073 1377 CAGGTGCAGCTGCAGGAGTCGGGCCCAAGACTGGTGA AGCCTTCGCAGACCCTGTCCCTCACCTGCACTGTCTCT GGTGGCTCCATCAGCAGTGGTGATTATTACTGGAGTT GGATCCGCCAGCCCCCAGGGAAGGGCCTGGAGTGGAT TGGGTACATCTATTACAGTGGGAGCACCCACTACAAC CCGTCCCTCAAGAGTCGAGTTAGCATGTCAGTAGACA CGGCCAAGAACCAGTTCTCCCTGAAGCTGACCTCTGT GACTGCCGCAGACACGGCCGTCTATTACTGTGCCAGA GATATCGGCTACGGTGACCACGGGACTGGGTCTTATT ACTACGGAATAGAAGACTGGGGCCAAGGGACCACGG TCACCGTCTCCTCA 318 5074 1378 QVQLQESGPRLVKPSQTLSLTCTVSGGSISSGDYYWSWI RQPPGKGLEWIGYIYYSGSTHYNPSLKSRVSMSVDTAKN QFSLKLTSVTAADTAVYYCARDIGYGDHGTGSYYYGIE DWGQGTTVTVSS 318 5075 1379 GSISSGDYYWS 318 5076 1380 GGCTCCATCAGCAGTGGTGATTATTACTGGAGT 318 5077 1381 YIYYSGSTHYNPSLKS 318 5078 1382 TACATCTATTACAGTGGGAGCACCCACTACAACCCGT CCCTCAAGAGT 318 5079 1383 ARDIGYGDHGTGSYYYGIED 318 5080 1384 GCCAGAGATATCGGCTACGGTGACCACGGGACTGGGT CTTATTACTACGGAATAGAAGAC 318 5081 1385 GATATTGTGATGACTCAGACTCCAGCCACCCTGTCTTT GTCTCCAGGGGACAGAGCCACCCTCTCCTGCAGGGCC AGTCAGAATATTATGAGCTACTTAGCCTGGTACCAAC ACAAACCTGGCCAGCCTCCCAGGCTCCTCATCTATGA TGCATCCTACAGGGCCGCTGGCATCCCAGCCAGGTTC AGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCA TCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTAC TGTCAGCAGCGAACCAACTGGATCACCTTCGGCCAAG GGACACGACTGGAGATTAAA 318 5082 1386 DIVMTQTPATLSLSPGDRATLSCRASQNIMSYLAWYQH KPGQPPRLLIYDASYRAAGIPARFSGSGSGTDFTLTISSLE PEDFAVYYCQQRTNWITFGQGTRLEIK 318 5083 1387 RASQNIMSYLA 318 5084 1388 AGGGCCAGTCAGAATATTATGAGCTACTTAGCC 318 5085 1389 DASYRAA 318 5086 1390 GATGCATCCTACAGGGCCGCT 318 5087 1391 QQRTNWIT 318 5088 1392 CAGCAGCGAACCAACTGGATCACC 319 5089 1393 GAGGTGCAGCTGGTGGAGTCAGGGGGAGGCTTGGTGC AGCGGGGGGGGTCCCTGAGACTCTCGTGTGCGGCCTC TGGATTCACCTTTAGTGGTAATGCCATGAGCTGGGTCC GCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGCATC TATTGGTGAAAGTGCTACTAGCGCATACTACGCAGAC TCCGTGAAGGGCCGGTTCACCATCTCCAGAGATGATT CGAAGAACACTCTGTATCTCCAAATGAACAGCCTGAG ACCCGAGGACACGGCCGTATATTTCTGTGCGAAAGAT CGCGTAGGATGGTTCGGGGAGTTCGACGCTTTTGATTT CTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA 319 5090 1394 EVQLVESGGGLVQRGGSLRLSCAASGFTFSGNAMSWVR QAPGKGLEWVASIGESATSAYYADSVKGRFTISRDDSKN TLYLQMNSLRPEDTAVYFCAKDRVGWFGEFDAFDFWG QGTMVTVSS 319 5091 1395 FTFSGNAMS 319 5092 1396 TTCACCTTTAGTGGTAATGCCATGAGC 319 5093 1397 SIGESATSAYYADSVKG 319 5094 1398 TCTATTGGTGAAAGTGCTACTAGCGCATACTACGCAG ACTCCGTGAAGGGC 319 5095 1399 AKDRVGWFGEFDAFDF 319 5096 1400 GCGAAAGATCGCGTAGGATGGTTCGGGGAGTTCGACG CTTTTGATTTC 319 5097 1401 TCCTATGAGCTGACGCAGCCACCCTCAGTGTCAGTGG CCCCAGGAAAGACGGCCACCATTTCCTGTGGGGGAAA CAACATTGGAGGTCACAAAGTGCACTGGTACCAGCAG AGGCCAGGCCAGGCCCCTGTCTTGGTCATCTATTATG ATAACGTCCGGCCCTCAGGGATCCCTGAGCGATTCTC TGGCTCCAACTCTGGAAACACGGCCACCCTGACCATC AGCAGGGTCGAGGCCGGGGATGAGGCCGACTTTTACT GTCAGGTGTGGGATAGTCGTTCTGAACATGTCATATTC GGCGGGGGGACCAAGGTCACCGTCCTA 319 5098 1402 SYELTQPPSVSVAPGKTATISCGGNNIGGHKVHWYQQRP GQAPVLVIYYDNVRPSGIPERFSGSNSGNTATLTISRVEA GDEADFYCQVWDSRSEHVIFGGGTKVTVL 319 5099 1403 GGNNIGGHKVH 319 5100 1404 GGGGGAAACAACATTGGAGGTCACAAAGTGCAC 319 5101 1405 YDNVRPS 319 5102 1406 TATGATAACGTCCGGCCCTCA 319 5103 1407 QVWDSRSEHVI 319 5104 1408 CAGGTGTGGGATAGTCGTTCTGAACATGTCATA 320 5105 1409 CAGGTCCAGCTTGTACAGTCTGGAGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCTCGTGCAAGACTTC TGGTTACACCTTTTCCAACTACGGTATCAGCTGGCTGC GACAGGCCCCTGGACAAGGGCTTGAGTGGATGGCATG GATCAGCCCTTATAATGGGAACACAAAGTCTGCACAG AGGTTTCAGGGCAGAGTCATCATGACCACAGACACAT CCACGAGGACAGCCCACATGGAGGTGAAGAGCCTGA GAACTGACGACACGGCCACATATTACTGTGCGAGAGA TCCAGCAGTCGATGCAATACCGATGCTTGACTACTGG GGCCAGGGAACCCTGGTCACCGTCTCCTCA 320 5106 1410 QVQLVQSGAEVKKPGASVKVSCKTSGYTFSNYGISWLR QAPGQGLEWMAWISPYNGNTKSAQRFQGRVIMTTDTST RTAHMEVKSLRTDDTATYYCARDPAVDAIPMLDYWGQ GTLVTVSS 320 5107 1411 YTFSNYGIS 320 5108 1412 TACACCTTTTCCAACTACGGTATCAGC 320 5109 1413 WISPYNGNTKSAQRFQG 320 5110 1414 TGGATCAGCCCTTATAATGGGAACACAAAGTCTGCAC AGAGGTTTCAGGGC 320 5111 1415 ARDPAVDAIPMLDY 320 5112 1416 GCGAGAGATCCAGCAGTCGATGCAATACCGATGCTTG ACTAC 320 5113 1417 GACATCCAGATGACCCAGTCTCCACTCTCCCTGCCCGT CACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTA GTCAAAGCCTCGTGTACACTGATGGAAACACCTACTT GAGCTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGG CGCCTAATTTATAGGGTTTCTCACCGGGACTCTGGGGT CCCAGACAGATTCACCGGCAGTGGGTCAGGCACTGAT TTCACACTGATAATCCGCAGGGTGGAGGCTGAGGATG TTGGGGTTTATTACTGCATGCAAGGTACACACTGGCCT CTCACTTTCGGCGGAGGGACCAAGCTGGAGATCAAA 320 5114 1418 DIQMTQSPLSLPVTLGQPASISCRSSQSLVYTDGNTYLSW FQQRPGQSPRRLIYRVSHRDSGVPDRFTGSGSGTDFTLIIR RVEAEDVGVYYCMQGTHWPLTFGGGTKLEIK 320 5115 1419 RSSQSLVYTDGNTYLS 320 5116 1420 AGGTCTAGTCAAAGCCTCGTGTACACTGATGGAAACA CCTACTTGAGC 320 5117 1421 RVSHRDS 320 5118 1422 AGGGTTTCTCACCGGGACTCT 320 5119 1423 MQGTHWPLT 320 5120 1424 ATGCAAGGTACACACTGGCCTCTCACT 321 5121 1425 CAGGTCCAGCTGGTACAGTCTGGTCCTGCGCTGGTGA AACCCACACAGACCCTCACACTGACCTGCACCTTCGG TGGATTCTCACTCAGCAGACATGGAATGCGTGTGACC TGGATCCGTCAGGCCCCCGGGAAGGCCCTGGAGTGGC TTGGTCACATTGATTGGGATGATGATAAATTCTACAG GACATCTCTGAAGACCAGGCTCACCATCTCCAAGGAC CCCTCTAACAATGAGGTGGTCCTGAAAATGACCAACA TGGACCACGTGGACACAGCCACGTATTACTGTGCACT GATGAGGCCCTTTTGGAGTCGTGACGACTACTACTATT CCATCGCCGTCTGGGGCAAAGGGACCACGGTCACCGT CTCCTCA 321 5122 1426 QVQLVQSGPALVKPTQTLTLTCTFGGFSLSRHGMRVTWI RQAPGKALEWLGHIDWDDDKFYRTSLKTRLTISKDPSN NEVVLKMTNMDHVDTATYYCALMRPFWSRDDYYYSIA VWGKGTTVTVSS 321 5123 1427 FSLSRHGMRVT 321 5124 1428 TTCTCACTCAGCAGACATGGAATGCGTGTGACC 321 5125 1429 HIDWDDDKFYRTSLKT 321 5126 1430 CACATTGATTGGGATGATGATAAATTCTACAGGACAT CTCTGAAGACC 321 5127 1431 ALMRPFWSRDDYYYSIAV 321 5128 1432 GCACTGATGAGGCCCTTTTGGAGTCGTGACGACTACT ACTATTCCATCGCCGTC 321 5129 1433 GATATTGTGCTGACCCAGTCTCCAGGCACCCTGTCTTT GTCTCCAGGGGACAGAGCCACCCTCTCCTGCAGGGCC AGTCAGAGTGTCGGCAGCGGCTACGTAACCTGGTACC AGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATTTA TGGTGCATCAAACAGGGCCGAAGGCATCCCAGACAG GTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTC ACCATCAGCGGACTGGAGTCTGAAGATTTTGTAATTT ATTACTGTCAGCTATATCATAGGTCACCTGGCTCTGCG AGTCAAACCGTTTGGACGTTCGGCCAAGGGACCAAGG TGGAAATCAAA 321 5130 1434 DIVLTQSPGTLSLSPGDRATLSCRASQSVGSGYVTWYQQ KPGQAPRLLIYGASNRAEGIPDRFSGSGSGTDFTLTISGLE SEDFVIYYCQLYHRSPGSASQTVWTFGQGTKVEIK 321 5131 1435 RASQSVGSGYVT 321 5132 1436 AGGGCCAGTCAGAGTGTCGGCAGCGGCTACGTAACC 321 5133 1437 GASNRAE 321 5134 1438 GGTGCATCAAACAGGGCCGAA 321 5135 1439 QLYHRSPGSASQTVWT 321 5136 1440 CAGCTATATCATAGGTCACCTGGCTCTGCGAGTCAAA CCGTTTGGACG 322 5137 1441 CAGGTCCAGCTTGTACAGTCTGGACCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAGGGTCTCCTGCGAGGCTTC TGGTTACCCCTTTAGCAATTACGGCATCACCTGGGTGC GCCAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATG GATCAGCGCTTACAACGGAAACAGAGACTATCTGCAG AAGTTTCAGGGCAGACTCACCATGACCATAGACACAT CCACGAGAACAGCCCACATGGAATTGAGGCGCCTGAC ATCTGACGACACGGCCGTATATTGGTGTGCGAGAGAC ACACCCGCCACTGCTGCCCCTCTGCTTGACTACTGGGG CCAGGGAACCCTGGTCACCGTCTCCTCA 322 5138 1442 QVQLVQSGPEVKKPGASVRVSCEASGYPFSNYGITWVR QAPGQGLEWMGWISAYNGNRDYLQKFQGRLTMTIDTS TRTAHMELRRLTSDDTAVYWCARDTPATAAPLLDYWG QGTLVTVSS 322 5139 1443 YPFSNYGIT 322 5140 1444 TACCCCTTTAGCAATTACGGCATCACC 322 5141 1445 WISAYNGNRDYLQKFQG 322 5142 1446 TGGATCAGCGCTTACAACGGAAACAGAGACTATCTGC AGAAGTTTCAGGGC 322 5143 1447 ARDTPATAAPLLDY 322 5144 1448 GCGAGAGACACACCCGCCACTGCTGCCCCTCTGCTTG ACTAC 322 5145 1449 GATATTGTGATGACTCAGTCTCCACTCTCCCTGGCCGT CACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTA GTCAAAGCCTCGAATTCACTGATGGAAACACCTACTT GAATTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGG CGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGT CCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGGT TTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATG TTGGGGTTTATTACTGCATGCAAGGTATTTTCCGGCCG GGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA 322 5146 1450 DIVMTQSPLSLAVTLGQPASISCRSSQSLEFTDGNTYLNW FQQRPGQSPRRLIYKVSNRDSGVPDRFSGSGSGTGFTLKI SRVEAEDVGVYYCMQGIFRPGTFGQGTKVEIK 322 5147 1451 RSSQSLEFTDGNTYLN 322 5148 1452 AGGTCTAGTCAAAGCCTCGAATTCACTGATGGAAACA CCTACTTGAAT 322 5149 1453 KVSNRDS 322 5150 1454 AAGGTTTCTAACCGGGACTCT 322 5151 1455 MQGIFRPGT 322 5152 1456 ATGCAAGGTATTTTCCGGCCGGGGACG 323 5153 1457 CAGGTCCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTC TGGTTACACCTTTGTCCACTATGGTATCAGTTGGGTGC GACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATG GATCAGCGCATACAATGGTAATACAAACTCTGCACTG AAGTTCCAGGACAGAGTCACCATGACCACAGACCCAT CCACGAGCACAGCCTACATGGAGCTGAGGAGCCTGAG ATCTGACGACACGGCCATTTATTACTGTGCGAGAGAC TCAGGTTGTTGTAGTGGTTCCACCTCAGACGTCTGGGG CAAAGGGACCACGGTCACCGTCTCCTCA 323 5154 1458 QVQLVQSGAEVKKPGASVKVSCKASGYTFVHYGISWVR QAPGQGLEWMGWISAYNGNTNSALKFQDRVTMTTDPS TSTAYMELRSLRSDDTAIYYCARDSGCCSGSTSDVWGK GTTVTVSS 323 5155 1459 YTFVHYGIS 323 5156 1460 TACACCTTTGTCCACTATGGTATCAGT 323 5157 1461 WISAYNGNTNSALKFQD 323 5158 1462 TGGATCAGCGCATACAATGGTAATACAAACTCTGCAC TGAAGTTCCAGGAC 323 5159 1463 ARDSGCCSGSTSDV 323 5160 1464 GCGAGAGACTCAGGTTGTTGTAGTGGTTCCACCTCAG ACGTC 323 5161 1465 GATATTGTGATGACTCAGTCTCCACTCTCTTCACCTGT CACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTA GTCAAAGCCTCGTGCACAGTGATGGAAACACCTACTT GAGTTGGCTTCACCAGAGGCCAGGCCAGCCTCCAAGA CTCCTAATTTATAAGATTTCCCACCGGTTCTCTGGGGT CCCAGACAGATTCACTGGCAGTGGGGCAGGGACAGAT TTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATG TCGGGGTTTATTACTGCATGCAAGCTACAGAATTTCCT CCGATGTACACTTTTGGCCAGGGGACCAAGGTGGAGA TCAAA 323 5162 1466 DIVMTQSPLSSPVTLGQPASISCRSSQSLVHSDGNTYLSW LHQRPGQPPRLLIYKISHRFSGVPDRFTGSGAGTDFTLKIS RVEAEDVGVYYCMQATEFPPMYTFGQGTKVEIK 323 5163 1467 RSSQSLVHSDGNTYLS 323 5164 1468 AGGTCTAGTCAAAGCCTCGTGCACAGTGATGGAAACA CCTACTTGAGT 323 5165 1469 KISHRFS 323 5166 1470 AAGATTTCCCACCGGTTCTCT 323 5167 1471 MQATEFPPMYT 323 5168 1472 ATGCAAGCTACAGAATTTCCTCCGATGTACACT 324 5169 1473 GAGGTGCAGCTGGTGGAGACGGGCCCAGGACTGGTG AAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTC TGGTGACTCCATCAGTGGTTACTACTGGAGCTGGATC CGGCAGTCCCCAGGGAAGGGACTGGAGTGGATTGGCT ATATCTATTACAGGGGGAGCACCGACTACAACCCCTC CCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCC AAGAACCAGTTCTCCCTGAAACTGAGCTCTGTGACCG CTGCGGACACGGCCGTGTATTACTGTGCGAGAGATAA TAAACACCATGATTCGGGAAATTATTACGCATACTTT GACCATTGGGGCCAGGGAACCCTGGTCACCGTCTCCT CA 324 5170 1474 EVQLVETGPGLVKPSETLSLTCTVSGDSISGYYWSWIRQ SPGKGLEWIGYIYYRGSTDYNPSLKSRVTISVDTSKNQFS LKLSSVTAADTAVYYCARDNKHHDSGNYYAYFDHWG QGTLVTVSS 324 5171 1475 DSISGYYWS 324 5172 1476 GACTCCATCAGTGGTTACTACTGGAGC 324 5173 1477 YIYYRGSTDYNPSLKS 324 5174 1478 TATATCTATTACAGGGGGAGCACCGACTACAACCCCT CCCTCAAGAGT 324 5175 1479 ARDNKHHDSGNYYAYFDH 324 5176 1480 GCGAGAGATAATAAACACCATGATTCGGGAAATTATT ACGCATACTTTGACCAT 324 5177 1481 GATATTGTGATGACTCAGTCTCCATCCTCCCTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCA AGTCAGAACATTAACACCTTTTTAAATTGGTATCAGC ACAAACCAGGGAAAGCCCCTAAACTCCTGATCTATGG TGCATCCCGTTTGCAGAGTGGGGTCCCATCAAGGTTC ACTGGCAGTGGATCTGGGACAGATTTCACTCTCACCA TCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTCC TGTCAACAGAGTTACACTACCCGGCTCACTTTCGGCG GAGGGACCAAGGTGGAAATCAAA 324 5178 1482 DIVMTQSPSSLSASVGDRVTITCRASQNINTFLNWYQHK PGKAPKLLIYGASRLQSGVPSRFTGSGSGTDFTLTISSLQP EDFATYSCQQSYTTRLTFGGGTKVEIK 324 5179 1483 RASQNINTFLN 324 5180 1484 CGGGCAAGTCAGAACATTAACACCTTTTTAAAT 324 5181 1485 GASRLQS 324 5182 1486 GGTGCATCCCGTTTGCAGAGT 324 5183 1487 QQSYTTRLT 324 5184 1488 CAACAGAGTTACACTACCCGGCTCACT 325 5185 1489 CAGGTCCAGCTGGTGCAGTCTGGGACTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGATTTCCTGCAAGACTTC TGGATACACCTTCACTAATAATGTAATTCAATGGGTG CGCCAGGCCCCCGGACAAAGGCTTGAGTGGATGGGAT GGATCAGCGCTGGCAATGGTTACACAAAATATTCAGA CAAGTTCCAGGACAGAGTCACCATTACCAGGGACACA TCCGCGAGCACAGCCTACATGGAGGTGAGCAGCCTGA CATCTGAAGACACGGCTATGTATTACTGTGCGAGACA AGTCTCGACTAGTGGCTGGCACGCAACGTCACACCGG TTCGCCCCCTGGGGCCAGGGAACCCTGGTCACCGTCT CCTCA 325 5186 1490 QVQLVQSGTEVKKPGASVKISCKTSGYTFTNNVIQWVR QAPGQRLEWMGWISAGNGYTKYSDKFQDRVTITRDTSA STAYMEVSSLTSEDTAMYYCARQVSTSGWHATSHRFAP WGQGTLVTVSS 325 5187 1491 YTFTNNVIQ 325 5188 1492 TACACCTTCACTAATAATGTAATTCAA 325 5189 1493 WISAGNGYTKYSDKFQD 325 5190 1494 TGGATCAGCGCTGGCAATGGTTACACAAAATATTCAG ACAAGTTCCAGGAC 325 5191 1495 ARQVSTSGWHATSHRFAP 325 5192 1496 GCGAGACAAGTCTCGACTAGTGGCTGGCACGCAACGT CACACCGGTTCGCCCCC 325 5193 1497 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCG AGTCAGGGCATTAGTAGATATTTAAATTGGTATCAGC AGAAACCAGGGAAAGCCCCTAACCTCCTGATCTACGA TGCATCCAATTTGGAAACAGGGGTCCCATCAAGGTTC AGTGGAAGTGGATCTGGGACACATTTTACTTTAACCA TCAGCAGCCTGCAGCCTGAAGATATTGCAACATATTA CTGTCAACAGTATGATAATCTCCCGCTCACTTTCGGCG GAGGGACCAAGGTGGAAATCAAA 325 5194 1498 DIQMTQSPSSLSASVGDRVTITCQASQGISRYLNWYQQK PGKAPNLLIYDASNLETGVPSRFSGSGSGTHFTLTISSLQP EDIATYYCQQYDNLPLTFGGGTKVEIK 325 5195 1499 QASQGISRYLN 325 5196 1500 CAGGCGAGTCAGGGCATTAGTAGATATTTAAAT 325 5197 1501 DASNLET 325 5198 1502 GATGCATCCAATTTGGAAACA 325 5199 1503 QQYDNLPLT 325 5200 1504 CAACAGTATGATAATCTCCCGCTCACT 326 5201 1505 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCC AGCCTGGGAGGTCCCTGAGACTCTCCTGTGAAGCCTC TGGATTCACCTTCAGTAGTTTTAGCATGCACTGGGTCC GCCAGGCTCCGGGCAAGGGGCTGGAGTGGGTGGCAG TGATTTTATATGATGGGAGTAATCAATACTATGCAGA CTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAAT TCCAAGAACACGCTTTATCTGCAAATGAACACCCTGA GAGCTGAGGACACGGCTATGTATTACTGTGCGAAATC ATCATCGTCCCATGTTAACTCTCGACAAGACAAATGG GGCCAGGGCACCCTGGTCACCGTCTCCTCA 326 5202 1506 EVQLVESGGGVVQPGRSLRLSCEASGFTFSSFSMHWVR QAPGKGLEWVAVILYDGSNQYYADSVKGRFTISRDNSK NTLYLQMNTLRAEDTAMYYCAKSSSSHVNSRQDKWGQ GTLVTVSS 326 5203 1507 FTFSSFSMH 326 5204 1508 TTCACCTTCAGTAGTTTTAGCATGCAC 326 5205 1509 VILYDGSNQYYADSVKG 326 5206 1510 GTGATTTTATATGATGGGAGTAATCAATACTATGCAG ACTCCGTGAAGGGC 326 5207 1511 AKSSSSHVNSRQDK 326 5208 1512 GCGAAATCATCATCGTCCCATGTTAACTCTCGACAAG ACAAA 326 5209 1513 GAAATTGTATTGACACAGTCTCCTTCCACCCTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCC AGTCAGAGTATTAGTAGGTGGTTGGCCTGGTATCAGC AGAAACCAGGGGAAGCCCCTAAACTCCTGATCCACAC GGCGTCTACATTAGAAAGTGGGGTCCCATCAAGGTTC AGCGGCAGTGGCTCTGGGACAGAATTCACTCTCACCA TCAACAGCCTGCAGCCTGATGATCTTGCAACTTATTAC TGCCAACAGTATTATAATTGGTGGACGTTCGGCCAAG GGACCAAGGTGGAGATCAAA 326 5210 1514 EIVLTQSPSTLSASVGDRVTITCRASQSISRWLAWYQQKP GEAPKLLIHTASTLESGVPSRFSGSGSGTEFTLTINSLQPD DLATYYCQQYYNWWTFGQGTKVEIK 326 5211 1515 RASQSISRWLA 326 5212 1516 CGGGCCAGTCAGAGTATTAGTAGGTGGTTGGCC 326 5213 1517 TASTLES 326 5214 1518 ACGGCGTCTACATTAGAAAGT 326 5215 1519 QQYYNWWT 326 5216 1520 CAACAGTATTATAATTGGTGGACG 327 5217 1521 GAGGTGCAGCTGTTGGAGTCCGGAGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGATCTCCTGCAAGGCCTC TGGTTACATCTTTACCAGTTATGGTGTCAGTTGGGTGC GACAGGCCCCTGGACAAGGGCTTAAGTGGATGGGATG GATCAGCGGTTACAATGGTAACACATACTATGACCAG AAATTCCAGGGCAGAGTCACCATGACCACAGACACAT CCACGAACACAGCCTACATGGAGTTGAGGAGCCTGAC ATCTGACGACACGGCCGTATATTACTGTGCGAGAGAT TCCTTTTCAGAGACTGGGACTGGATTTCCTGACTTCTG GGGCCAGGGCACCCTGGTCACCGTCTCTTCA 327 5218 1522 EVQLLESGAEVKKPGASVKISCKASGYIFTSYGVSWVRQ APGQGLKWMGWISGYNGNTYYDQKFQGRVTMTTDTST NTAYMELRSLTSDDTAVYYCARDSFSETGTGFPDFWGQ GTLVTVSS 327 5219 1523 YIFTSYGVS 327 5220 1524 TACATCTTTACCAGTTATGGTGTCAGT 327 5221 1525 WISGYNGNTYYDQKFQG 327 5222 1526 TGGATCAGCGGTTACAATGGTAACACATACTATGACC AGAAATTCCAGGGC 327 5223 1527 ARDSFSETGTGFPDF 327 5224 1528 GCGAGAGATTCCTTTTCAGAGACTGGGACTGGATTTC CTGACTTC 327 5225 1529 GAAATTGTGTTGACGCAGTCTCCACTCTCCCTGCCCGT CACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTA GTCAAAGCCTCGAATACAGTGATGGAAACACCTACTT GAATTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGG CGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGT CCCCGACAGATTCAGCGGCAGTGGGTCAGGCACTGAT TTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATG TTGGAGTTTATTACTGCATGCAAGCCACACACCGGCC TCGCACGTTCGGCCAAGGGACCAAAGTGGATATCAAA 327 5226 1530 EIVLTQSPLSLPVTLGQPASISCRSSQSLEYSDGNTYLNW FQQRPGQSPRRLIYKVSNRDSGVPDRFSGSGSGTDFTLKI SRVEAEDVGVYYCMQATHRPRTFGQGTKVDIK 327 5227 1531 RSSQSLEYSDGNTYLN 327 5228 1532 AGGTCTAGTCAAAGCCTCGAATACAGTGATGGAAACA CCTACTTGAAT 327 5229 1533 KVSNRDS 327 5230 1534 AAGGTTTCTAACCGGGACTCT 327 5231 1535 MQATHRPRT 327 5232 1536 ATGCAAGCCACACACCGGCCTCGCACG 328 5233 1537 CAGGTCCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAA AGCCCGGGGAGTCTCTGAAGATCTCCTGTAAGGGTTT TGGATACAGCTTTAACAGTTACTGGATCGCCTGGGTG CGCCAGATGCCCGGGAAAGGCCTGGAGTGCATGGGC ATCATCTATCCTGGCGACTCTGATACCAGATACAGCC CGTCCTTCCAAGGGCAGGTCACCATCTCAGTCGACAA GTCCATCACTACCGCCTACCTGCAGTGGAGCAGCCTG AAGGTCTCGGACACCGCCATGTATTACTGTGCGAAAA GTAATGTGGGGAATACAGGTTGGAACTACTGGGGCCA GGGAACCCTGGTCACCGTCTCCTCA 328 5234 1538 QVQLVQSGAEVKKPGESLKISCKGFGYSFNSYWIAWVR QMPGKGLECMGIIYPGDSDTRYSPSFQGQVTISVDKSITT AYLQWSSLKVSDTAMYYCAKSNVGNTGWNYWGQGTL VTVSS 328 5235 1539 YSFNSYWIA 328 5236 1540 TACAGCTTTAACAGTTACTGGATCGCC 328 5237 1541 IIYPGDSDTRYSPSFQG 328 5238 1542 ATCATCTATCCTGGCGACTCTGATACCAGATACAGCC CGTCCTTCCAAGGG 328 5239 1543 AKSNVGNTGWNY 328 5240 1544 GCGAAAAGTAATGTGGGGAATACAGGTTGGAACTAC 328 5241 1545 GAAATTGTATTGACACAGTCTCCAGCCACCCTGTCTTT GTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC AGTCACAGTGTTGCCACCGACCTAGCCTGGTACCAGC AGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGA TGCATCCAAGAGGGCCACTGACGTCCCAGCCAGGTTC AGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCA TCAGCAGCCTAGAGCCTGAAGATGTTGCAGTTTATTA CTGTCAGGAAGTTAGGAACTGGCCTCCGTGCACTTTT GGCCAGGGGACCAAAGTGGATATCAAA 328 5242 1546 EIVLTQSPATLSLSPGERATLSCRASHSVATDLAWYQQK PGQAPRLLIYDASKRATDVPARFSGSGSGTDFTLTISSLEP EDVAVYYCQEVRNWPPCTFGQGTKVDIK 328 5243 1547 RASHSVATDLA 328 5244 1548 AGGGCCAGTCACAGTGTTGCCACCGACCTAGCC 328 5245 1549 DASKRAT 328 5246 1550 GATGCATCCAAGAGGGCCACT 328 5247 1551 QEVRNWPPCT 328 5248 1552 CAGGAAGTTAGGAACTGGCCTCCGTGCACT 329 5249 1553 GAGGTGCAGCTGCAGGAGTCCGGCTCTCGACTGGTGA AGCCTTCACAGACCCTGTCCCTCACCTGCTCTGTCTCT GGTGGCTCCCTCAACGCAGGCGGTTACCTGTGGAGCT GGATCCGTCAGCCACCAGGGAAGGGCCTGGAGTGGGT TGGGTACATCTATCCTAGTGGGACTACCTACTACAAC CCGTCCCTGCAGAGTCGAATCAGCATTTCACAAGACA GGTCCAGGAACCAGTTCTCCCTGAGCGTAGCGTCTGT GACCGCCGCGGACACGGCCGTCTATTACTGTGCCAGA TGTGGGAATGAGTACGGTGAGGTCCATCCTTTTGATA TTTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 329 5250 1554 EVQLQESGSRLVKPSQTLSLTCSVSGGSLNAGGYLWSWI RQPPGKGLEWVGYIYPSGTTYYNPSLQSRISISQDRSRNQ FSLSVASVTAADTAVYYCARCGNEYGEVHPFDIWGQGT TVTVSS 329 5251 1555 GSLNAGGYLWS 329 5252 1556 GGCTCCCTCAACGCAGGCGGTTACCTGTGGAGC 329 5253 1557 YIYPSGTTYYNPSLQS 329 5254 1558 TACATCTATCCTAGTGGGACTACCTACTACAACCCGTC CCTGCAGAGT 329 5255 1559 ARCGNEYGEVHPFDI 329 5256 1560 GCCAGATGTGGGAATGAGTACGGTGAGGTCCATCCTT TTGATATT 329 5257 1561 GAAATTGTATTGACACAGTCTCCAGGCACCCTGTCTTT GTCTCCAGGGGAAAGAGCCACCCTCTCCTGCCGGGGC AGTCCTATTGTTGGCAACAACTACTTAGCCTGGTACCA GCAGAAGCCTGGCCAGGCTCCCAGGCTCCTCATCTAT GCTGCATCCATCAGGGCCACTGGCATCCCAGACAGGT TCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCAC CATCAGCAGACTAGAGCCTGAAGATTTTGCAGTCTAT TACTGTCAGCAATATGGCAGCTCACCGTGGACGTTCG GCCAAGGGACCAAAGTGGATATCAAA 329 5258 1562 EIVLTQSPGTLSLSPGERATLSCRGSPIVGNNYLAWYQQ KPGQAPRLLIYAASIRATGIPDRFSGSGSGTDFTLTISRLE PEDFAVYYCQQYGSSPWTFGQGTKVDIK 329 5259 1563 RGSPIVGNNYLA 329 5260 1564 CGGGGCAGTCCTATTGTTGGCAACAACTACTTAGCC 329 5261 1565 AASIRAT 329 5262 1566 GCTGCATCCATCAGGGCCACT 329 5263 1567 QQYGSSPWT 329 5264 1568 CAGCAATATGGCAGCTCACCGTGGACG 330 5265 1569 CAGGTGCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTC TGGTTACATCTTTACCAGTTATGGTGTCAGCTGGGTGC GACAGGCCCCTGGACAAGGGCTTAAGTGGATGGGATG GATCAGCGGTTACAATGGTAACACAAACTATGACCAG AAACTCCAGGGCAGAGTCACCATGACCACAGACACAT CCACGAGCACAGCCTACATGGAGCTGAGGAGCCTGAC ATCTGACGACACGGCCGTTTATTACTGTGCGAGAGAT TCATTTTCAGAGACTGGGACTGGGTTTCCTGACTTCTG GGGCCAGGGAACCCTGGTCACCGTCTCCTCA 330 5266 1570 QVQLVQSGAEVKKPGASVKVSCKASGYIFTSYGVSWVR QAPGQGLKWMGWISGYNGNTNYDQKLQGRVTMTTDT STSTAYMELRSLTSDDTAVYYCARDSFSETGTGFPDFWG QGTLVTVSS 330 5267 1571 YIFTSYGVS 330 5268 1572 TACATCTTTACCAGTTATGGTGTCAGC 330 5269 1573 WISGYNGNTNYDQKLQG 330 5270 1574 TGGATCAGCGGTTACAATGGTAACACAAACTATGACC AGAAACTCCAGGGC 330 5271 1575 ARDSFSETGTGFPDF 330 5272 1576 GCGAGAGATTCATTTTCAGAGACTGGGACTGGGTTTC CTGACTTC 330 5273 1577 GACATCCAGATGACCCAGTCTCCACTCTCCCTGCCCGT CACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTA GTCAAAGCCTCGAATACAGTGATGGAAACACCTACTT GAATTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGG CGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGT CCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGAT TTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATG TTGGAGTTTATTACTGCATGCAAGCCACACACCGGCC TCGCACGTTCGGCCAAGGGACCAAGCTGGAGATCAAA 330 5274 1578 DIQMTQSPLSLPVTLGQPASISCRSSQSLEYSDGNTYLNW FQQRPGQSPRRLIYKVSNRDSGVPDRFSGSGSGTDFTLKI SRVEAEDVGVYYCMQATHRPRTFGQGTKLEIK 330 5275 1579 RSSQSLEYSDGNTYLN 330 5276 1580 AGGTCTAGTCAAAGCCTCGAATACAGTGATGGAAACA CCTACTTGAAT 330 5277 1581 KVSNRDS 330 5278 1582 AAGGTTTCTAACCGGGACTCT 330 5279 1583 MQATHRPRT 330 5280 1584 ATGCAAGCCACACACCGGCCTCGCACG 331 5281 1585 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCC AGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTC TGGATTCACCTTCAGTAGTTTTTCTATGCACTGGGTCC GCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCACT TATATCATCTGACGAGAGGAATTCATACTACGCAGAC TCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATT CCAAGAACACGCTGTATCTGCAAATAAGCAGGCTGAA AGTCGAGGACACGGCTGTGTATTATTGTGCGAGAGAG GCATACGAAGAGTGGGAGCTAACGATGGGGAACCTT GACCACTGGGGCCAGGGAACCCTGGTCACCGTCTCCT CA 331 5282 1586 EVQLVESGGGVVQPGRSLRLSCAASGFTFSSFSMHWVR QAPGKGLEWVALISSDERNSYYADSVKGRFTISRDNSKN TLYLQISRLKVEDTAVYYCAREAYEEWELTMGNLDHW GQGTLVTVSS 331 5283 1587 FTFSSFSMH 331 5284 1588 TTCACCTTCAGTAGTTTTTCTATGCAC 331 5285 1589 LISSDERNSYYADSVKG 331 5286 1590 CTTATATCATCTGACGAGAGGAATTCATACTACGCAG ACTCCGTGAAGGGC 331 5287 1591 AREAYEEWELTMGNLDH 331 5288 1592 GCGAGAGAGGCATACGAAGAGTGGGAGCTAACGATG GGGAACCTTGACCAC 331 5289 1593 GACATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCA AGTCAGGGCATTGGAAATGATTTAGGCTGGTATCAGC AGAAACCAGGGAAAGCCCCTAAGCGCCTGATCTATAG TACATACAGCTTGCAAAGTGGGGTCCCATCAAGGTTC AGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAA TCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTAC TGTCTACAGCATAATCGTTACCCCTTCACTTTCGGCCC TGGGACCAAGCTGGAGATCAAA 331 5290 1594 DIQLTQSPSSLSASVGDRVTITCRASQGIGNDLGWYQQK PGKAPKRLIYSTYSLQSGVPSRFSGSGSGTEFTLTISSLQP EDFATYYCLQHNRYPFTFGPGTKLEIK 331 5291 1595 RASQGIGNDLG 331 5292 1596 CGGGCAAGTCAGGGCATTGGAAATGATTTAGGC 331 5293 1597 STYSLQS 331 5294 1598 AGTACATACAGCTTGCAAAGT 331 5295 1599 LQHNRYPFT 331 5296 1600 CTACAGCATAATCGTTACCCCTTCACT 332 5297 1601 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGA AGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCT GGTGCCTCCGTCACCACTAATACTTACTACTGGACCTG GATCCGGCAGCCCCCAGGGAAGGAACTGGAGTGGATT GGATATATCCATCACACTGGGAACACCCACTACAACC CCTCCCTCGAGAGTCGACTCACCATGTCACTAGACAC GTCCAGGAACCAGTTCTCTCTGAACCTTAGGTCTGCCA CCACTGCGGACACGGCCGTTTATTACTGTGCGAGAGG CGAACATTTTGCGTACTGGTGGGGAAACTGGGGCCAG GGAGCCCTGGTCACCGTCTCCTCA 332 5298 1602 QVQLQESGPGLVKPSETLSLTCTVSGASVTTNTYYWTWI RQPPGKELEWIGYIHHTGNTHYNPSLESRLTMSLDTSRN QFSLNLRSATTADTAVYYCARGEHFAYWWGNWGQGA LVTVSS 332 5299 1603 ASVTTNTYYWT 332 5300 1604 GCCTCCGTCACCACTAATACTTACTACTGGACC 332 5301 1605 YIHHTGNTHYNPSLES 332 5302 1606 TATATCCATCACACTGGGAACACCCACTACAACCCCT CCCTCGAGAGT 332 5303 1607 ARGEHFAYWWGN 332 5304 1608 GCGAGAGGCGAACATTTTGCGTACTGGTGGGGAAAC 332 5305 1609 GACATCCGGGTGACCCAGTCTCCATCTTCCGTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCG AGTCAGGGTATTGCCAGATGGTTAGCCTGGTATCAGC AGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATGC TGCATCCAGTTTGCAAGGTGGGGTCCCATCAAGGTTC AGCGGCAGTGGATATGGGACAGATTTCACTCTCACCA TCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTA CTGTCAACAGGCTAACAGTTTTCCTCGAACGTTCGGCC AAGGGACCAAGGTGGAGATCAAA 332 5306 1610 DIRVTQSPSSVSASVGDRVTITCRASQGIARWLAWYQQK PGKAPKLLIYAASSLQGGVPSRFSGSGYGTDFTLTISSLQ PEDFATYYCQQANSFPRTFGQGTKVEIK 332 5307 1611 RASQGIARWLA 332 5308 1612 CGGGCGAGTCAGGGTATTGCCAGATGGTTAGCC 332 5309 1613 AASSLQG 332 5310 1614 GCTGCATCCAGTTTGCAAGGT 332 5311 1615 QQANSFPRT 332 5312 1616 CAACAGGCTAACAGTTTTCCTCGAACG 333 5313 1617 CAGGTCCAGCTTGTACAGTCTGGGCCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCTCCTGCGAGGCTTC TGGATACACCTTCACCGACTTCTTTGTGCACTGGGTGC GACAGGCCCCTGGTGAGGGGCTTGTGTGGTTGGGATG GGTCAACCCTCTCAGTGGCGCCACAAAGTATGCACAG AACTTTCAGGGCAGGGTCACCATGACCAGTGACACGT CCATCACCACAGCCTACATGGCACTGAGCAGCCTGAG ACATGACGACACGGCCGTCTATTACTGTACGAGCCAG ACTTCACCTTATACCCCGGGCGCTATGGGCGTTTGGG GCCAAGGGACCACGGTCACCGTCTCCTCA 333 5314 1618 QVQLVQSGPEVKKPGASVKVSCEASGYTFTDFFVHWVR QAPGEGLVWLGWVNPLSGATKYAQNFQGRVTMTSDTS ITTAYMALSSLRHDDTAVYYCTSQTSPYTPGAMGVWGQ GTTVTVSS 333 5315 1619 YTFTDFFVH 333 5316 1620 TACACCTTCACCGACTTCTTTGTGCAC 333 5317 1621 WVNPLSGATKYAQNFQG 333 5318 1622 TGGGTCAACCCTCTCAGTGGCGCCACAAAGTATGCAC AGAACTTTCAGGGC 333 5319 1623 TSQTSPYTPGAMGV 333 5320 1624 ACGAGCCAGACTTCACCTTATACCCCGGGCGCTATGG GCGTT 333 5321 1625 GACATCCGGGTGACCCAGTCTCCAGCCTCCCTGTCTGC ATTTGTTGGAGACAGAGTCACCATCACTTGCCGGGCA AGTCCGGCCATTAGCGGCTATTTAAGTTGGTATCAGC AGAAGGCAGGCAAAGCCCCTAAGATCCTGATCTATGA TGCATCTAATTTGTATAGTGGGGCCCCATCACGGTTCA GTGGCAGTAGATCTGGGACAGATTTCACTCTCACCAT CACCAGTCTGCAACCTGAAGATTTTGCAACTTACTACT GTCAACAGACTTACAATGGCCTAATCGCTTTCGGCCCT GGGACCAAGGTGGAAATCAAA 333 5322 1626 DIRVTQSPASLSAFVGDRVTITCRASPAISGYLSWYQQKA GKAPKILIYDASNLYSGAPSRFSGSRSGTDFTLTITSLQPE DFATYYCQQTYNGLIAFGPGTKVEIK 333 5323 1627 RASPAISGYLS 333 5324 1628 CGGGCAAGTCCGGCCATTAGCGGCTATTTAAGT 333 5325 1629 DASNLYS 333 5326 1630 GATGCATCTAATTTGTATAGT 333 5327 1631 QQTYNGLIA 333 5328 1632 CAACAGACTTACAATGGCCTAATCGCT 334 5329 1633 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCGTGGTCC AGCCTGGGAAGTCCCTGAGACTCTCCTGTGCAGCCTC TGGATTCACCTTCAATACCTATGCTATACACTGGGTCC GCCAGGCTCCAGGCAAGGGCCTGGAGTGGGTGGCAG CTATATCATATGATGGAAGCAATGAATACTACTCAAA CTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAAT TCCAAGTACACGCTGGAGCTGCAAATGAACAGCCTGA GACCTGAGGACACGGCTGTGTATTACTGTGCGAGAGG CGCCTCCTACTACTATGTGAGTAGTGACCTTGGCTACT GGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 334 5330 1634 EVQLLESGGGVVQPGKSLRLSCAASGFTFNTYAIHWVR QAPGKGLEWVAAISYDGSNEYYSNSVKGRFTISRDNSK YTLELQMNSLRPEDTAVYYCARGASYYYVSSDLGYWG QGTLVTVSS 334 5331 1635 FTFNTYAIH 334 5332 1636 TTCACCTTCAATACCTATGCTATACAC 334 5333 1637 AISYDGSNEYYSNSVKG 334 5334 1638 GCTATATCATATGATGGAAGCAATGAATACTACTCAA ACTCCGTGAAGGGC 334 5335 1639 ARGASYYYVSSDLGY 334 5336 1640 GCGAGAGGCGCCTCCTACTACTATGTGAGTAGTGACC TTGGCTAC 334 5337 1641 CAGTCTGTCGTGACGCAGCCGCCCTCAGTGTCTGGGG CCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAG CAGCTCCAACATCGGGTCAGGTTATGATGTGCACTGG TACCAGCAGCTTCCAGGAACAGCCCCCAAAGTCGTCA TCTATGGTAACATCAATCGGCCCTCAGGGGTCCCTGA GCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCC TGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGA TTATTACTGCCAGTCCTATGACAGCCTGAGTGCCTCTT GGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA 334 5338 1642 QSVVTQPPSVSGAPGQRVTISCTGSSSNIGSGYDVHWYQ QLPGTAPKVVIYGNINRPSGVPERFSGSKSGTSASLAITG LQAEDEADYYCQSYDSLSASWVFGGGTKLTVL 334 5339 1643 TGSSSNIGSGYDVH 334 5340 1644 ACTGGGAGCAGCTCCAACATCGGGTCAGGTTATGATG TGCAC 334 5341 1645 GNINRPS 334 5342 1646 GGTAACATCAATCGGCCCTCA 334 5343 1647 QSYDSLSASWV 334 5344 1648 CAGTCCTATGACAGCCTGAGTGCCTCTTGGGTG 335 5345 1649 CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGA AGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCCTC TGGAGGCACCTTCAGCGGCCACGCTATCAACTGGGTG CGACAGGCCCCTGGACAAGGGCTCGAATGGATGGGA GGGATCATCCATATATTTGGGACAGTAAACTACGCTC CGAAGTTCCAGGGCAGAGTCACGATCACCGCGGACGC ATCCACGGGCACAGTTTACATGGAGTTGAGCAGCCTG ATATCTGAGGACACGGCCGTATATTATTGTGCGAGAG ATGCTTACGAAGTGTGGACTGGTTCTTATCTCCCCCCT TTTGACGACTGGGGCCAGGGAACCCTGGTCACTGTCT CCTCA 335 5346 1650 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSGHAINWVR QAPGQGLEWMGGIIHIFGTVNYAPKFQGRVTITADASTG TVYMELSSLISEDTAVYYCARDAYEVWTGSYLPPFDDW GQGTLVTVSS 335 5347 1651 GTFSGHAIN 335 5348 1652 GGCACCTTCAGCGGCCACGCTATCAAC 335 5349 1653 GIIHIFGTVNYAPKFQG 335 5350 1654 GGGATCATCCATATATTTGGGACAGTAAACTACGCTC CGAAGTTCCAGGGC 335 5351 1655 ARDAYEVWTGSYLPPFDD 335 5352 1656 GCGAGAGATGCTTACGAAGTGTGGACTGGTTCTTATC TCCCCCCTTTTGACGAC 335 5353 1657 GATATTGTGATGACGCAGTCTCCAGGCACCCTGTCTTT GTCTCCCGGGGACAGAGTCACCCTCTCCTGCAGGGCC AGTCAGACTGTTACAAGCAGCTACTTAGCCTGGTACC AGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTA TGGTGCATTCACCAGGGCCACTGGCATCCCAGACAGG TTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCA GCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTATA TTATTGTCAGCAGTATGGTAGCTCATTCCTCACTTTCG GCGGAGGGACCAAAGTGGATATCAAA 335 5354 1658 DIVMTQSPGTLSLSPGDRVTLSCRASQTVTSSYLAWYQQ KPGQAPRLLIYGAFTRATGIPDRFSGSGSGTDFTLSISRLE PEDFAVYYCQQYGSSFLTFGGGTKVDIK 335 5355 1659 RASQTVTSSYLA 335 5356 1660 AGGGCCAGTCAGACTGTTACAAGCAGCTACTTAGCC 335 5357 1661 GAFTRAT 335 5358 1662 GGTGCATTCACCAGGGCCACT 335 5359 1663 QQYGSSFLT 335 5360 1664 CAGCAGTATGGTAGCTCATTCCTCACT 336 5361 1665 GAGGTGCAGCTGGTGGAATCTGGGGGAGGCCTGGTCA GGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTC TGGATTCAGTCTCAGTAGTTACGGCATGAGTTGGGTC CGCCAGGCTCCAGGGAAGGGTCTGGAGTGGGTCTCAT CCATTACTGCCGGCAGTAGTTACATAAATTACGCTGA CTCAGTGAAGGGCCGGTTCACCATCTCCAGAGACAAC GCCAAGAGTTCACTGTTCCTGCAAATGACCAGCCTGA GAGTCGAGGACACGGCTGTTTATTTCTGTGTGAGAGA GGCGTATGCCAGCTCGTCGGCCCTTTACTGGTTCGACC CCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 336 5362 1666 EVQLVESGGGLVRPGGSLRLSCAASGFSLSSYGMSWVR QAPGKGLEWVSSITAGSSYINYADSVKGRFTISRDNAKS SLFLQMTSLRVEDTAVYFCVREAYASSSALYWFDPWGQ GTLVTVSS 336 5363 1667 FSLSSYGMS 336 5364 1668 TTCAGTCTCAGTAGTTACGGCATGAGT 336 5365 1669 SITAGSSYINYADSVKG 336 5366 1670 TCCATTACTGCCGGCAGTAGTTACATAAATTACGCTG ACTCAGTGAAGGGC 336 5367 1671 VREAYASSSALYWFDP 336 5368 1672 GTGAGAGAGGCGTATGCCAGCTCGTCGGCCCTTTACT GGTTCGACCCC 336 5369 1673 CAGTCTGTCCTGACGCAGCCGCCCTCAGTCTCTGGGG CCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAG CAGCTCCAATCTCGGGGCGGGTTATGTTGTTCACTGGT ACCAGCAACTTCCAGGAACATCCCCCAAACTCCTCAT CTATGGTAACACCGATCGGCCCTCAGGGGTCCCCGAC CGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCT GGCCATCAGTGGGCTCCAGGCTGAGGATGAGGCTGAT TATTACTGCCAGTCCTATGACAGTAGCCTGAGTGGCT GGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA 336 5370 1674 QSVLTQPPSVSGAPGQRVTISCTGSSSNLGAGYVVHWYQ QLPGTSPKLLIYGNTDRPSGVPDRFSGSKSGTSASLAISGL QAEDEADYYCQSYDSSLSGWVFGGGTKLTVL 336 5371 1675 TGSSSNLGAGYVVH 336 5372 1676 ACTGGGAGCAGCTCCAATCTCGGGGCGGGTTATGTTG TTCAC 336 5373 1677 GNTDRPS 336 5374 1678 GGTAACACCGATCGGCCCTCA 336 5375 1679 QSYDSSLSGWV 336 5376 1680 CAGTCCTATGACAGTAGCCTGAGTGGCTGGGTG 337 5377 1681 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTAGTAC AGCCTGGGGGGTCCCTGCGACTCTCCTGTGCAGCCTCT GGATTCAGCTTCAATACCTATAGCATGAACTGGGTCC GCCAGGCTCCAGGGAAGGGATTGGAGTGGCTTTCATT CATTAGTAGTAGTAGTCATACCCTATACTACGCAGAC TCTGTGAAGGGCCGATTCACCGTCTTCAGAGACAATG CCAAGCACTCGCTCTTTCTGCAAATGAACGGCCTGAG AGACGAGGACACGGCTGTTTATTTCTGTGCGAGATCC CTTGGTTCGGGGAATTATGATAACGAAGATCAGACAT TTTACTACTACTACGGTATGGACGTCTGGGGCCAAGG GACCACGGTCACCGTCTCCTCA 337 5378 1682 EVQLVESGGGLVQPGGSLRLSCAASGFSFNTYSMNWVR QAPGKGLEWLSFISSSSHTLYYADSVKGRFTVFRDNAKH SLFLQMNGLRDEDTAVYFCARSLGSGNYDNEDQTFYYY YGMDVWGQGTTVTVSS 337 5379 1683 FSFNTYSMN 337 5380 1684 TTCAGCTTCAATACCTATAGCATGAAC 337 5381 1685 FISSSSHTLYYADSVKG 337 5382 1686 TTCATTAGTAGTAGTAGTCATACCCTATACTACGCAGA CTCTGTGAAGGGC 337 5383 1687 ARSLGSGNYDNEDQTFYYYYGMDV 337 5384 1688 GCGAGATCCCTTGGTTCGGGGAATTATGATAACGAAG ATCAGACATTTTACTACTACTACGGTATGGACGTC 337 5385 1689 GAAACGACACTCACGCAGTCTCCACTCTCCCTGCCCG TCACCCCTGGAGAGCCGGCCTCCATATCCTGCCGGTCT AGTCAGAGCCTCCTGTTTCATAGTAATGGACACAATT ATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTCTCC ACAACTCCTGATCCATTTGGGTTCTAATCGGGCCTCCG GAGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCAC AGATTTTACACTGAAAATCAGCAGAGTGGAGCCTGAG GATGTTGGGGTTTATTACTGTATGCAAGCTCTACAAAC TCCGTACACTTTTGGCCAGGGGACCAAGGTGGAGATC AAA 337 5386 1690 ETTLTQSPLSLPVTPGEPASISCRSSQSLLFHSNGHNYLD WYLQKPGQSPQLLIHLGSNRASGVPDRFSGSGSGTDFTL KISRVEPEDVGVYYCMQALQTPYTFGQGTKVEIK 337 5387 1691 RSSQSLLFHSNGHNYLD 337 5388 1692 CGGTCTAGTCAGAGCCTCCTGTTTCATAGTAATGGAC ACAATTATTTGGAT 337 5389 1693 LGSNRAS 337 5390 1694 TTGGGTTCTAATCGGGCCTCC 337 5391 1695 MQALQTPYT 337 5392 1696 ATGCAAGCTCTACAAACTCCGTACACT 338 5393 1697 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACGGGTG AAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTC TGGTGTCTCCGTCACCATTAATGATTACTACTGGACTT GGCTCCGCCAGTCCCCAGGGAAAGGCCTGGAGTGGAT TGGAAACATCTATAACAGTGGGAGCACCTACCAGAAC CCGTCCCTCCAGAGTCGAGTTACCATGTCAGTGGACA CGGCCAAGAACCACTTCTCCCTGAAGCTGACCTCTGT CACTGCCGCAGATACGGCCGTCTATTACTGTGCCAGA GATTTAGGCACTGCCAACAACTACTACTTCGGTATGG ACGTCTGGGGCCTAGGGACCACGGTCACCGTCTCCTC A 338 5394 1698 QVQLQESGPGRVKPSQTLSLTCTVSGVSVTINDYYWTW LRQSPGKGLEWIGNIYNSGSTYQNPSLQSRVTMSVDTAK NHFSLKLTSVTAADTAVYYCARDLGTANNYYFGMDVW GLGTTVTVSS 338 5395 1699 VSVTINDYYWT 338 5396 1700 GTCTCCGTCACCATTAATGATTACTACTGGACT 338 5397 1701 NIYNSGSTYQNPSLQS 338 5398 1702 AACATCTATAACAGTGGGAGCACCTACCAGAACCCGT CCCTCCAGAGT 338 5399 1703 ARDLGTANNYYFGMDV 338 5400 1704 GCCAGAGATTTAGGCACTGCCAACAACTACTACTTCG GTATGGACGTC 338 5401 1705 GATATTGTGCTGACGCAGTCTCCAGCCACCCTGTCTTT GTCTCCAGGGGAAAGAGCCACTCTCTCCTGCAGGGCC AGTCAGAGTGTTAGCACCTACTTAGCCTGGTACCAAC AGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATAA TGGATCCAACAGGGTCACTGGCACCCCAGCCAGGTTC AGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCA TCAGCAGCGTAGAGCCTGAAGATTTTGCAGTTTATTA CTGTCAGCAGCGTAGCAACTGGCCTCCGTACACTTTTG GCCAGGGGACCAAGGTGGAGATCAAA 338 5402 1706 DIVLTQSPATLSLSPGERATLSCRASQSVSTYLAWYQQK PGQAPRLLIYNGSNRVTGTPARFSGSGSGTDFTLTISSVEP EDFAVYYCQQRSNWPPYTFGQGTKVEIK 338 5403 1707 RASQSVSTYLA 338 5404 1708 AGGGCCAGTCAGAGTGTTAGCACCTACTTAGCC 338 5405 1709 NGSNRVT 338 5406 1710 AATGGATCCAACAGGGTCACT 338 5407 1711 QQRSNWPPYT 338 5408 1712 CAGCAGCGTAGCAACTGGCCTCCGTACACT 339 5409 1713 GAGGTGCAGCTGGTGGAGTCGGGCCCTGGACTGGTGA AGCCTTCAGAGACCCTGTCCCTCAGTTGCATTGTCTCT GGTGACTCCATCACCAGTAATGATTACTACTGGAGTT GGATCCGCCAGTCCCCAGGGAAGGGCCTGGAGTGGAT TGGGTACATCTATCACAGCGGGGCCACCTTCTACACT CCGTCCCTACGGAGTCGAGTGACCATATCGACAGACA GGTCCAAGAACCAGTTCTCCCTGAGACTGTCGTCTGT GACCGCCGCAGACACGGCCGTATATTATTGTGCCAGT GGACCTGTGGGGATGGCTACAAGCAACTGGTTCGACC CCTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCA 339 5410 1714 EVQLVESGPGLVKPSETLSLSCIVSGDSITSNDYYWSWIR QSPGKGLEWIGYIYHSGATFYTPSLRSRVTISTDRSKNQF SLRLSSVTAADTAVYYCASGPVGMATSNWFDPWGQGT LVTVSS 339 5411 1715 DSITSNDYYWS 339 5412 1716 GACTCCATCACCAGTAATGATTACTACTGGAGT 339 5413 1717 YIYHSGATFYTPSLRS 339 5414 1718 TACATCTATCACAGCGGGGCCACCTTCTACACTCCGTC CCTACGGAGT 339 5415 1719 ASGPVGMATSNWFDP 339 5416 1720 GCCAGTGGACCTGTGGGGATGGCTACAAGCAACTGGT TCGACCCC 339 5417 1721 CAGCCTGTGCTGACTCAGCCACCCTCAGTGTCAGTCG CCCCGGGAAAGACGGCCACTCTTACGTGTGGGGGAGA CATCATTAGAACTAACAGTGTGAACTGGTACCAGCAG AAGCCAGGCCAGGCCCCTGTATTGATCATATATTATG ATAGCGACCGGCCCTCAGGGATCCCTGGGCGATTCTC TGCCTCCAACTCTGGGAGCGCGGCCACCCTGACCATC AGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACT GTCAGGTGTGGGACAGCAGTACTGATTATCACGTGGT TTTCGGCGGAGGGACCAAGCTCACCGTCCTA 339 5418 1722 QPVLTQPPSVSVAPGKTATLTCGGDIIRTNSVNWYQQKP GQAPVLIIYYDSDRPSGIPGRFSASNSGSAATLTISRVEAG DEADYYCQVWDSSTDYHVVFGGGTKLTVL 339 5419 1723 GGDIIRTNSVN 339 5420 1724 GGGGGAGACATCATTAGAACTAACAGTGTGAAC 339 5421 1725 YDSDRPS 339 5422 1726 TATGATAGCGACCGGCCCTCA 339 5423 1727 QVWDSSTDYHVV 339 5424 1728 CAGGTGTGGGACAGCAGTACTGATTATCACGTGGTT CAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCATC TGGATACATCTTCACCGGTTATTTTATACACTGGGTGC GACAGGCCCCCGGACAAGGGCTTGAGTGGATGGGAG TAATCAATCCCAGAGGTGGAAGCACAAGCTACGCACA 340 5425 1729 AAAGTTCCAGGGCAGAGTCGCTGTGTCCAGGGACACG TCCACGACTACAGTCTACATGGAGCTGAACAGCCTGA GATCTGAGGACACGGCCGTATATTACTGTGCGAGAGC CCCGAGCCACGATGAGTGGGTCGCAATTTCCCGAAAT AACGATGTTGTGGGGTTCGACGCCTGGGGCCAGGGAA CCCTGGTCACCGTCTCCTCA 340 5426 1730 QVQLVQSGAEVKKPGASVKVSCKASGYIFTGYFIHWVR QAPGQGLEWMGVINPRGGSTSYAQKFQGRVAVSRDTST TTVYMELNSLRSEDTAVYYCARAPSHDEWVAISRNNDV VGFDAWGQGTLVTVSS 340 5427 1731 YIFTGYFIH 340 5428 1732 TACATCTTCACCGGTTATTTTATACAC 340 5429 1733 VINPRGGSTSYAQKFQG 340 5430 1734 GTAATCAATCCCAGAGGTGGAAGCACAAGCTACGCAC AAAAGTTCCAGGGC 340 5431 1735 ARAPSHDEWVAISRNNDVVGFDA 340 5432 1736 GCGAGAGCCCCGAGCCACGATGAGTGGGTCGCAATTT CCCGAAATAACGATGTTGTGGGGTTCGACGCC 340 5433 1737 CAGTCTGTCCTGACTCAGCCGCCCTCAGTGTCTGGGGC CCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGGGC AGCTCCAACATCGGGGCAGATTATGACGTACACTGGT ACCAGCAGCCTCCAGGAACAGCCCCCAAACTCCTCAT ATTTGCTAACAACAATCGACCCTCAGGGGTCCCTGGC CGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCT GGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGAT TATTACTGCCAGTCCTATGACAGCAGCCTGAGTGCTTG GGTGTTCGGCGGGGGGACCAAGCTGACCGTCCTA 340 5434 1738 QSVLTQPPSVSGAPGQRVTISCTGGSSNIGADYDVHWYQ QPPGTAPKLLIFANNNRPSGVPGRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSSLSAWVFGGGTKLTVL 340 5435 1739 TGGSSNIGADYDVH 340 5436 1740 ACTGGGGGCAGCTCCAACATCGGGGCAGATTATGACG TACAC 340 5437 1741 ANNNRPS 340 5438 1742 GCTAACAACAATCGACCCTCA 340 5439 1743 QSYDSSLSAWV 340 5440 1744 CAGTCCTATGACAGCAGCCTGAGTGCTTGGGTG 341 5441 1745 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCA AGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTC TGGATTCACCCTCAGTAGTTATGCCATGAACTGGGTCC GCCAGGCTCCAGGGAAGGGTCTGGAGTGGGTCTCATC CATTAGTGCTGGAAGTAGTTACATCGACTACGCAGAC TCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACG CCAAGAACTCTCTGTATCTGCAAATGAACAACCTGAG AGCCGAGGACACGGCTCTGTATTACTGTGCGAGAGAA GTTTTACCAGCAACCGCTATAGGAGGCGCCTGGCTCG ACCCCTGGGGCCAGGGAACCCTGGTCACTGTCTCCTC A 341 5442 1746 EVQLVESGGGLVKPGGSLRLSCAASGFTLSSYAMNWVR QAPGKGLEWVSSISAGSSYIDYADSVKGRFTISRDNAKN SLYLQMNNLRAEDTALYYCAREVLPATAIGGAWLDPW GQGTLVTVSS 341 5443 1747 FTLSSYAMN 341 5444 1748 TTCACCCTCAGTAGTTATGCCATGAAC 341 5445 1749 SISAGSSYIDYADSVKG 341 5446 1750 TCCATTAGTGCTGGAAGTAGTTACATCGACTACGCAG ACTCAGTGAAGGGC 341 5447 1751 AREVLPATAIGGAWLDP 341 5448 1752 GCGAGAGAAGTTTTACCAGCAACCGCTATAGGAGGCG CCTGGCTCGACCCC 341 5449 1753 CAGTCTGTCCTGACGCAGCCGCCCTCAGTGTCTGGGG CCCCAGGGCAGACGGTCACCATCTCCTGCACTGGGAG CAGCTCCAACATCGGGGCTGGATATGATGTCCACTGG TACCGGCAGCTTCCAGGAACAGCCCCCAAACTCCTCA TCTATTCTAACAACAATCGGCCCTCAGGGGTCCCTGA CCGATTCTCTGGCTCCAAGTCTGACACCTCAGCCTCCC TGGCCATCACTGGGCTCCAGGCTGGGGATGAGGCTGA TTATTACTGCCAGTCCTATGACATCAGCCTGAGTGCCT CTTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCT A 341 5450 1754 QSVLTQPPSVSGAPGQTVTISCTGSSSNIGAGYDVHWYR QLPGTAPKLLIYSNNNRPSGVPDRFSGSKSDTSASLAITG LQAGDEADYYCQSYDISLSASYVFGTGTKVTVL 341 5451 1755 TGSSSNIGAGYDVH 341 5452 1756 ACTGGGAGCAGCTCCAACATCGGGGCTGGATATGATG TCCAC 341 5453 1757 SNNNRPS 341 5454 1758 TCTAACAACAATCGGCCCTCA 341 5455 1759 QSYDISLSASYV 341 5456 1760 CAGTCCTATGACATCAGCCTGAGTGCCTCTTATGTC 342 5457 1761 CAGGTCCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTC TGGTTACACCTTTACCAACTATGGTTTCAGCTGGGTGC GACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATG GATCCTCACTCACAATGGTTACACAAACTATGCACAG AAGTTCCAGGACAGAGTCACCATGAAGACAGACACAT CCACGAGCACAGTCTACATGGAGCTGAGGAGCCTGAG ATCTGTCGACACGGCCGTGTATTACTGTGCGAGAATT GGCCATGTTACAGCCGTGGCTGGTGCCCCTCCTGACT ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 342 5458 1762 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGFSWV RQAPGQGLEWMGWILTHNGYTNYAQKFQDRVTMKTD TSTSTVYMELRSLRSVDTAVYYCARIGHVTAVAGAPPD YWGQGTLVTVSS 342 5459 1763 YTFTNYGFS 342 5460 1764 TACACCTTTACCAACTATGGTTTCAGC 342 5461 1765 WILTHNGYTNYAQKFQD 342 5462 1766 TGGATCCTCACTCACAATGGTTACACAAACTATGCAC AGAAGTTCCAGGAC 342 5463 1767 ARIGHVTAVAGAPPDY 342 5464 1768 GCGAGAATTGGCCATGTTACAGCCGTGGCTGGTGCCC CTCCTGACTAC 342 5465 1769 CAGCCTGTGCTGACTCAGCCTGCCTCCGTGTCTGGGTA TCAAGGACAGTCGATCACCATCTCCTGCAGTGGAACC AGCAGTGATGTTGGGACTTATAACCTTGTCTCCTGGTA CCAACAACACCCAGGCAAAGCCCCCGAACTCATGATT TATGAGGGCAGTAAGCGGCCCTCAGGGGTTTCTGATC GCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTG ACAATCTCTGGGCTCCAGGCTGAGGACGAGGCTGATT ATTACTGCTGCTCATATGTAGCTGGTAGTACTTCAGTA TTCGGCGGAGGGACCAAGCTCACCGTCCTA 342 5466 1770 QPVLTQPASVSGYQGQSITISCSGTSSDVGTYNLVSWYQ QHPGKAPELMIYEGSKRPSGVSDRFSGSKSGNTASLTISG LQAEDEADYYCCSYVAGSTSVFGGGTKLTVL 342 5467 1771 SGTSSDVGTYNLVS 342 5468 1772 AGTGGAACCAGCAGTGATGTTGGGACTTATAACCTTG TCTCC 342 5469 1773 EGSKRPS 342 5470 1774 GAGGGCAGTAAGCGGCCCTCA 342 5471 1775 CSYVAGSTSV 342 5472 1776 TGCTCATATGTAGCTGGTAGTACTTCAGTA 343 5473 1777 GAGGTGCAGCTGGTGGAGTCGGGCCCTGGACTGGTGA AGCCTTCAGAGACCCTGTCCCTCAGTTGCATTGTCTCT GGTGGCTCCATCACCAGTGGTGATTACTACTGGAGTT GGCTCCGCCAGTCCCCAGGGAAGGGCCTGGAGTGGAT TGGGTACATATATCACAGCGGGGCCACCTTCTACACC CCGTCCCTACGGAGTCGAGTGACCATTTCGACAGACA CCTCCAAGAACCAATTCTCCCTGAGACTGTCGTCTGTG ACCGCCGCAGACACGGCCGTTTATTATTGTGCCAGTG GACCTGTCGGGATGGCTACAAGCAACTGGTTCGACCC CTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 343 5474 1778 EVQLVESGPGLVKPSETLSLSCIVSGGSITSGDYYWSWLR QSPGKGLEWIGYIYHSGATFYTPSLRSRVTISTDTSKNQF SLRLSSVTAADTAVYYCASGPVGMATSNWFDPWGQGT LVTVSS 343 5475 1779 GSITSGDYYWS 343 5476 1780 GGCTCCATCACCAGTGGTGATTACTACTGGAGT 343 5477 1781 YIYHSGATFYTPSLRS 343 5478 1782 TACATATATCACAGCGGGGCCACCTTCTACACCCCGT CCCTACGGAGT 343 5479 1783 ASGPVGMATSNWFDP 343 5480 1784 GCCAGTGGACCTGTCGGGATGGCTACAAGCAACTGGT TCGACCCC 343 5481 1785 TCCTATGAGCTGACACAGCCACCCTCAGTATCAGTCG CCCCGGGAAAGACGGCCACCATTACGTGTGGGGGAG ACATCATTAGAACTAACAGTGTGAACTGGTACCAGCA GAAGCCAGGCCAGGCCCCTCTATTGCTCATCTATTATG ATAGCGACCGGCCCTCAGGGATCCCTGAGCGATTCTC TGCCTCCAACTCTGGGAACACGGCCACCCTGACCATC AGCAGGGTCGAGGCCGGGGATGAGGCCGACTATTACT GTCAGGTGTGGGACAGTGGTACTGATTATCACGTGGT TTTCGGCGGAGGGACCAAGCTGACCGTCCAA 343 5482 1786 SYELTQPPSVSVAPGKTATITCGGDIIRTNSVNWYQQKP GQAPLLLIYYDSDRPSGIPERFSASNSGNTATLTISRVEAG DEADYYCQVWDSGTDYHVVFGGGTKLTVQ 343 5483 1787 GGDIIRTNSVN 343 5484 1788 GGGGGAGACATCATTAGAACTAACAGTGTGAAC 343 5485 1789 YDSDRPS 343 5486 1790 TATGATAGCGACCGGCCCTCA 343 5487 1791 QVWDSGTDYHVV 343 5488 1792 CAGGTGTGGGACAGTGGTACTGATTATCACGTGGTT 344 5489 1793 CAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGA GGCCTGGGGCCTCAGTGAAAGTCTCCTGCAAGGCTTC TGAATACGCCTTCACCGCCCACTATCTTCACTGGGTGC GACAGGCCCCTGATCAAGGACTTGAGTGGATGGGATG GATCAGCCCTAAAAGTGGTGGCACCAACTATGCACAG AAGTTTCACGGCAGGGTCAGCATGACCAGTGACACGT CCATCAGTACAGTCTATATGGAACTGAGCAGCCTGAC ATCTGACGACACGGCCGTCTATTACTGTGCGAGAAGC AGTCTGGTGGGAGCAAGCCCCAACTTTGACTTCTGGG GCCAGGGAACCCTGGTCACCGTCTCCTCA 344 5490 1794 QVQLVQSGAEVKRPGASVKVSCKASEYAFTAHYLHWV RQAPDQGLEWMGWISPKSGGTNYAQKFHGRVSMTSDT SISTVYMELSSLTSDDTAVYYCARSSLVGASPNFDFWGQ GTLVTVSS 344 5491 1795 YAFTAHYLH 344 5492 1796 TACGCCTTCACCGCCCACTATCTTCAC 344 5493 1797 WISPKSGGTNYAQKFHG 344 5494 1798 TGGATCAGCCCTAAAAGTGGTGGCACCAACTATGCAC AGAAGTTTCACGGC 344 5495 1799 ARSSLVGASPNFDF 344 5496 1800 GCGAGAAGCAGTCTGGTGGGAGCAAGCCCCAACTTTG ACTTC 344 5497 1801 CAGTCTGTGGTGACGCAGCCGCCCTCAGTGTCTGCGG CCCCAGGACAGAGGGTCACCATCTCCTGCTCTGGAAG CAGCTCCAACATTGGGAATAATTATGTATCCTGGTAC CAGCAACTCCCAGGATCTACCCCCAAAGTCCTCATTT ACGACAATAATCAGCGACCCTCAGGGATTCCTGACCG TTTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGG CCATCAGCGGACTCCAGACTGGCGACGAGGCCGTCTA TTATTGCGGAACATGGGATGCCAGCCTGAGTGCTGCA ATGGTTTTCGGCGGGGGGACCAAGCTCACCGTCCTA 344 5498 1802 QSVVTQPPSVSAAPGQRVTISCSGSSSNIGNNYVSWYQQ LPGSTPKVLIYDNNQRPSGIPDRFSGSKSGTSATLAISGLQ TGDEAVYYCGTWDASLSAAMVFGGGTKLTVL 344 5499 1803 SGSSSNIGNNYVS 344 5500 1804 TCTGGAAGCAGCTCCAACATTGGGAATAATTATGTAT CC 344 5501 1805 DNNQRPS 344 5502 1806 GACAATAATCAGCGACCCTCA 344 5503 1807 GTWDASLSAAMV 344 5504 1808 GGAACATGGGATGCCAGCCTGAGTGCTGCAATGGTT 345 5505 1809 CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGA AGCCTTCGGAGACCCTGTCCCTAACCTGCGCTGTCTCT GGTGGGTACTTCATTAATGACAACTGGAGCTGGATCC GCCAGTCCCCAGGGAAGGGGCTGGAGTGGATTGGAG AAATTAGTCATAGTGGAAGCACCAACTACAATCCGTC CCTCAAGAGTCGACTCACCATATCAGTTGACACGTCC AGGCAGCAGTTTTCCCTGAAATTGAGCTCTGTGACCG CCGCGGACAGTGGTGTTTACTACTGTGCGCGAGTCCA CCCGTCGTATGACTTTGGCTGGCGCTTCTTTGACTTCT GGGGCCAGGGAACCCTGGTCACCGTCTCTTCA 345 5506 1810 QVQLQQWGAGLLKPSETLSLTCAVSGGYFINDNWSWIR QSPGKGLEWIGEISHSGSTNYNPSLKSRLTISVDTSRQQFS LKLSSVTAADSGVYYCARVHPSYDFGWRFFDFWGQGTL VTVSS 345 5507 1811 GYFINDNWS 345 5508 1812 GGGTACTTCATTAATGACAACTGGAGC 345 5509 1813 EISHSGSTNYNPSLKS 345 5510 1814 GAAATTAGTCATAGTGGAAGCACCAACTACAATCCGT CCCTCAAGAGT 345 5511 1815 ARVHPSYDFGWRFFDF 345 5512 1816 GCGCGAGTCCACCCGTCGTATGACTTTGGCTGGCGCTT CTTTGACTTC 345 5513 1817 GAAACGACACTCACGCAGTCTCCAGCCACCCTGTCTG TGTCTCCAGGGGATACAGCCACCCTCTCCTGCAGGGC CAGTCAGACTATTAGTTCCAACTTAGCCTGGTACCAG CAGAAACCTGGCCAGCCTCCCAGTCTCCTCATCTATG GAGCATCCAACAGGGCCACTGGTATCCCAGACAGGTT TCGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACC ATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTA CTGTCAGCAGTATGCATACTGGCCTCCGTACACTTTTG GCCAGGGGACCAAGGTGGAGATCAAA 345 5514 1818 ETTLTQSPATLSVSPGDTATLSCRASQTISSNLAWYQQKP GQPPSLLIYGASNRATGIPDRFRGSGSGTEFTLTISSLQSE DFAVYYCQQYAYWPPYTFGQGTKVEIK 345 5515 1819 RASQTISSNLA 345 5516 1820 AGGGCCAGTCAGACTATTAGTTCCAACTTAGCC 345 5517 1821 GASNRAT 345 5518 1822 GGAGCATCCAACAGGGCCACT 345 5519 1823 QQYAYWPPYT 345 5520 1824 CAGCAGTATGCATACTGGCCTCCGTACACT 346 5521 1825 GAGGTGCAGCTGTTGGAGTCGGGCCCAGGACTGGTGA AGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCG GGTGGCTCCATCAACAGTATTGATTATTATTGGAGCTG GATCCGCCAGCCCCCAGGGAAGGGCCTGGAGTGGATT GGCTACATTTATCACAGTGGGAGCACCCACTACAGAC CATCCCTCAAGAGTCGAGTAACGATATCATTAGACAA GGCCAAGAACGAGTTCTCGCTGAGTCTGACCTCTGTG ACTGCCGCAGACACGGCCGTGTATTTCTGTGCCAGTG GCCCCGTCGGGATGGCAACAAGCAACTGGTTCGACCC CTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 346 5522 1826 EVQLLESGPGLVKPSQTLSLTCTVSGGSINSIDYYWSWIR QPPGKGLEWIGYIYHSGSTHYRPSLKSRVTISLDKAKNEF SLSLTSVTAADTAVYFCASGPVGMATSNWFDPWGQGTL VTVSS 346 5523 1827 GSINSIDYYWS 346 5524 1828 GGCTCCATCAACAGTATTGATTATTATTGGAGC 346 5525 1829 YIYHSGSTHYRPSLKS 346 5526 1830 TACATTTATCACAGTGGGAGCACCCACTACAGACCAT CCCTCAAGAGT 346 5527 1831 ASGPVGMATSNWFDP 346 5528 1832 GCCAGTGGCCCCGTCGGGATGGCAACAAGCAACTGGT TCGACCCC 346 5529 1833 CAGCCTGTGCTGACTCAGCCACCCTCAGTGTCAGTGA CCCCAGGAGAGACGGCCAGGCTTCCCTGTGAGGGAGA CATCGTTGTCACTAACAGTGTCCACTGGTACCAGCAG AAGCCAGGCCAGGCCCCTGTTTTGGTCGTCTATTATGA TAGCGACCGGGCCTCAGGGATCCCTGAGCGATTCTCT GGCTCCAATTCTGGGAACACGGCCACCCTGAGCATCA GCAGGGTCGAAGCCGGGGATGAGGCCGACTACTATTG TCAGGTGTGGGATAGTAGTACTGATCATCATGTGGTG TTCGGCGGTGGGACCAAGCTCACCGTCCTA 346 5530 1834 QPVLTQPPSVSVTPGETARLPCEGDIVVTNSVHWYQQKP GQAPVLVVYYDSDRASGIPERFSGSNSGNTATLSISRVEA GDEADYYCQVWDSSTDHHVVFGGGTKLTVL 346 5531 1835 EGDIVVTNSVH 346 5532 1836 GAGGGAGACATCGTTGTCACTAACAGTGTCCAC 346 5533 1837 YDSDRAS 346 5534 1838 TATGATAGCGACCGGGCCTCA 346 5535 1839 QVWDSSTDHHVV 346 5536 1840 CAGGTGTGGGATAGTAGTACTGATCATCATGTGGTG 347 5537 1841 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGA AGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTC TGGAGGCAGATTCAGCAGCGACGCTATCAGCTGGGTG CGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGA GGAATCATCCCTATCCGTGGGACACCAACCTACGCAC AGAAGTTCCAGGGCAGAGTCACGATTATCGCGGACGA ATCCACGACTACATCCTACATGGAGATGAGCAGCCTG AGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAC CGAATTACGATATTTTGACTGGTTATAATGATGCTTTT GATATTTGGGGCCAAGGGACAATGGTCACCGTCTCTT CA 347 5538 1842 QVQLVQSGAEVKKPGSSVKVSCKASGGRFSSDAISWVR QAPGQGLEWMGGIIPIRGTPTYAQKFQGRVTIIADESTTT SYMEMSSLRSEDTAVYYCARPNYDILTGYNDAFDIWGQ GTMVTVSS 347 5539 1843 GRFSSDAIS 347 5540 1844 GGCAGATTCAGCAGCGACGCTATCAGC 347 5541 1845 GIIPIRGTPTYAQKFQG 347 5542 1846 GGAATCATCCCTATCCGTGGGACACCAACCTACGCAC AGAAGTTCCAGGGC 347 5543 1847 ARPNYDILTGYNDAFDI 347 5544 1848 GCGAGACCGAATTACGATATTTTGACTGGTTATAATG ATGCTTTTGATATT 347 5545 1849 CAGTCTGTGTTGACGCAGCCTCGCTCAGTGTCCGGGTC TCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACC AGCAGTGATGTTGGTGGTTATAACTATGTCTCCTGGTA CCAACAGCACCCAGGCAAAGTCCCCAGACTCATGATT TACGATGTCAGTAAGCGGCCCTCAGGGGCCCCTGATC GCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTG ACCATCTCTGGGCTCCAGGCTGAGGATGAGGCTGATT ATTACTGCTGCTCATATGCAGGCGGCCTTTATGTCTTC GGAACTGGGACCAAGCTCACCGTCCTA 347 5546 1850 QSVLTQPRSVSGSPGQSVTISCTGTSSDVGGYNYVSWYQ QHPGKVPRLMIYDVSKRPSGAPDRFSGSKSGNTASLTISG LQAEDEADYYCCSYAGGLYVFGTGTKLTVL 347 5547 1851 TGTSSDVGGYNYVS 347 5548 1852 ACTGGAACCAGCAGTGATGTTGGTGGTTATAACTATG TCTCC 347 5549 1853 DVSKRPS 347 5550 1854 GATGTCAGTAAGCGGCCCTCA 347 5551 1855 CSYAGGLYV 347 5552 1856 TGCTCATATGCAGGCGGCCTTTATGTC 348 5553 1857 GAGGTGCAGCTGGTGGAGTCCGGGGCTGAGGTGAAG AAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTT CTGGATACACCTTCACCACTTATGATATCAACTGGGTG CGACAGGCCACTGGACGGGGGCTTGAGTGGATGGGAT GGATGACCCCTGATAGTGGTAGCACAGGCTATCCACA GAACTTCCAGGGCAGAGTCACCATGACCAGGAACACC TCCATAAGCACAGCCTACATGGAGTTGAGCAACCTGA GATCTGAGGACACGGCCGTATATTACTGTGTGCAAAT GGACCATTGTAGAAGTACCAGCTGCTCTGAGGGGAAC TGGTTCGACACCTGGGGCCAGGGAACCCTGGTCACCG TCTCCTCA 348 5554 1858 EVQLVESGAEVKKPGASVKVSCKASGYTFTTYDINWVR QATGRGLEWMGWMTPDSGSTGYPQNFQGRVTMTRNTS ISTAYMELSNLRSEDTAVYYCVQMDHCRSTSCSEGNWF DTWGQGTLVTVSS 348 5555 1859 YTFTTYDIN 348 5556 1860 TACACCTTCACCACTTATGATATCAAC 348 5557 1861 WMTPDSGSTGYPQNFQG 348 5558 1862 TGGATGACCCCTGATAGTGGTAGCACAGGCTATCCAC AGAACTTCCAGGGC 348 5559 1863 VQMDHCRSTSCSEGNWFDT 348 5560 1864 GTGCAAATGGACCATTGTAGAAGTACCAGCTGCTCTG AGGGGAACTGGTTCGACACC 348 5561 1865 CAGCCTGGGCTGACTCAGCCACCCTCGGTGTCTGCAG CCCCCAGGCAGAGGGTCACCATCTCCTGTTCTGGAAG CAGCTCCAACATCGGAACTAATGCTGTAAACTGGTAC CAGCAGCTCCCAGGAAAGGCTCCCAAACTCCTCATCT ATTCTGATAATCTGATGCCCTCAGGGGTCTCTGCCCGA TTCTCTGGCTCCAAGTCTGGCACCTCGGCCTCCCTGGC CATCAGTGGGCTCCAGTCTGAGGATGAGGCTGATTAT TACTGTGCAGCATGGGATGACAGCCTGAATGTTTGGG TGTTCGGCGGGGGGACCAAGCTCACCGTCCTA 348 5562 1866 QPGLTQPPSVSAAPRQRVTISCSGSSSNIGTNAVNWYQQ LPGKAPKLLIYSDNLMPSGVSARFSGSKSGTSASLAISGL QSEDEADYYCAAWDDSLNVWVFGGGTKLTVL 348 5563 1867 SGSSSNIGTNAVN 348 5564 1868 TCTGGAAGCAGCTCCAACATCGGAACTAATGCTGTAA AC 348 5565 1869 SDNLMPS 348 5566 1870 TCTGATAATCTGATGCCCTCA 348 5567 1871 AAWDDSLNVWV 348 5568 1872 GCAGCATGGGATGACAGCCTGAATGTTTGGGTG 349 5569 1873 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTGA AGCCAGGGCGGTCCCTGAGACTCTCCTGTACAGCCTC TGGATTCAACTTCGGTGATTATGCTATGAGCTGGTTCC GCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTAGGTTT CATTAGAAGCAAAACTTATCGTGAGACAAGAGAATAC GCCGCGTCTGTGAAAGGCAGATTCACCATGTCAAGAG ATGATTTCAACAGGATCGCCTATCTGCAAATGAACAG CCTGAAAACCGAGGACACAGCCATGTATTATTGTACG AGACAAGACGATTTTTGGAGTGGTCATCCCTACTACTT TGAGTACTGGGGCCAGGGAACCCTGGTCACCGTCTCC TCA 349 5570 1874 EVQLVESGGGLVKPGRSLRLSCTASGFNFGDYAMSWFR QAPGKGLEWVGFIRSKTYRETREYAASVKGRFTMSRDD FNRIAYLQMNSLKTEDTAMYYCTRQDDFWSGHPYYFEY WGQGTLVTVSS 349 5571 1875 FNFGDYAMS 349 5572 1876 TTCAACTTCGGTGATTATGCTATGAGC 349 5573 1877 FIRSKTYRETREYAASVKG 349 5574 1878 TTCATTAGAAGCAAAACTTATCGTGAGACAAGAGAAT ACGCCGCGTCTGTGAAAGGC 349 5575 1879 TRQDDFWSGHPYYFEY 349 5576 1880 ACGAGACAAGACGATTTTTGGAGTGGTCATCCCTACT ACTTTGAGTAC 349 5577 1881 CAGCCTGTGCTGACTCAGCCCCCCTCCGCGTCCGGGTC TCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACC AACAGTGACGTGGGTAGTTATAACTATGTCTCCTGGT ACCAACATCACCCAGGCAAAGCCCCCAAACTCATCAT TTATGACGTCGCTAAGCGGCCCTCAGGGGTCCCTGAT CGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCT GACCGTCTCTGGGCTCCAGGCTGAGGATGAGGCTGAT TATTACTGCAGCTCATATGCAGGCAGTAACGATTTGG GGGTCTTCGGAACTGGGACCAAGCTCACCGTCCTA 349 5578 1882 QPVLTQPPSASGSPGQSVTISCTGTNSDVGSYNYVSWYQ HHPGKAPKLIIYDVAKRPSGVPDRFSGSKSGNTASLTVS GLQAEDEADYYCSSYAGSNDLGVFGTGTKLTVL 349 5579 1883 TGTNSDVGSYNYVS 349 5580 1884 ACTGGAACCAACAGTGACGTGGGTAGTTATAACTATG TCTCC 349 5581 1885 DVAKRPS 349 5582 1886 GACGTCGCTAAGCGGCCCTCA 349 5583 1887 SSYAGSNDLGV 349 5584 1888 AGCTCATATGCAGGCAGTAACGATTTGGGGGTC 350 5585 1889 GAGGTGCAGCTGGTGGAGTCCGGCCCAGGACTGGTGA AGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTGTCT GGTGGCTCCGTCAGTGGTCACTACTGGAGCTGGATTC GGCAGTTCCCAGGGAAGGAACTGGAATGGATTGGTCA TATCTATTATATTGGGACGACCAACTACAACCCCTCCC TCAAGAGTCGAGTCATCATATCGCTAGACACGTCCAA GAATCAGCTCTCCCTGAAGCTGAGTTCTGTGACCGCT GCGGACACTGCCGTTTATTATTGTGCCAGACAGTTCG GCTATGATAAAAATACTTTAAGTCGGCTTGACTTTGAC TACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 350 5586 1890 EVQLVESGPGLVKPSETLSLTCTVSGGSVSGHYWSWIRQ FPGKELEWIGHIYYIGTTNYNPSLKSRVIISLDTSKNQLSL KLSSVTAADTAVYYCARQFGYDKNTLSRLDFDYWGQG TLVTVSS 350 5587 1891 GSVSGHYWS 350 5588 1892 GGCTCCGTCAGTGGTCACTACTGGAGC 350 5589 1893 HIYYIGTTNYNPSLKS 350 5590 1894 CATATCTATTATATTGGGACGACCAACTACAACCCCTC CCTCAAGAGT 350 5591 1895 ARQFGYDKNTLSRLDFDY 350 5592 1896 GCCAGACAGTTCGGCTATGATAAAAATACTTTAAGTC GGCTTGACTTTGACTAC 350 5593 1897 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC ATCTGTAAGAGACAGAGTCACCATCACTTGCCGGGCA AGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAAC AGAGACCAGGGAAAGCCCCTAAGCTCCTGATCTATTC TGCATTCAGTTTACATAGTGGTGTCCCATCAAGGTTCA GTGGCAGTGGATCTGAGACAGAGTTCACTCTCACCAT CAGCAGTCTGCAACCTGACGATTTTGCAACTTATTACT GTCAACAGAGTTACAGTATTCCCTGGACGTTCGGCCA AGGGACCAAGGTGGAAATCAAA 350 5594 1898 DIQMTQSPSSLSASVRDRVTITCRASQSISSYLNWYQQRP GKAPKLLIYSAFSLHSGVPSRFSGSGSETEFTLTISSLQPD DFATYYCQQSYSIPWTFGQGTKVEIK 350 5595 1899 RASQSISSYLN 350 5596 1900 CGGGCAAGTCAGAGCATTAGCAGCTATTTAAAT 350 5597 1901 SAFSLHS 350 5598 1902 TCTGCATTCAGTTTACATAGT 350 5599 1903 QQSYSIPWT 350 5600 1904 CAACAGAGTTACAGTATTCCCTGGACG 351 5601 1905 CAGGTGCAGCTGCAGGAGTCCGGCCCGGGACTGGTGA AGCCTTCGGAGACCCTGTCCCTCACCTGCAGTGTCTCT GGTGGCTCCATCACCAATGTTAATTACTACTGGGGCT GGATCCGCCAGCCCCCCGGGAAGGGCCTGGAGTGGAT TGGGAGTATCTATTATAATGGAAACACCTACTACAAC CCGTCCCTCCAGAGTCGAGTCACCATGTCCGTGGACA CGTCCAAGAACCACTTCTCCCTGAGGCTGACGTCTGT GACCGCCGCAGACACGGCTGTATATTTTTGTGCGAGA GAGGGGCCTAATTGGGAATTGTTGAATGCTTTCGATA TCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 351 5602 1906 QVQLQESGPGLVKPSETLSLTCSVSGGSITNVNYYWGWI RQPPGKGLEWIGSIYYNGNTYYNPSLQSRVTMSVDTSKN HFSLRLTSVTAADTAVYFCAREGPNWELLNAFDIWGQG TTVTVSS 351 5603 1907 GSITNVNYYWG 351 5604 1908 GGCTCCATCACCAATGTTAATTACTACTGGGGC 351 5605 1909 SIYYNGNTYYNPSLQS 351 5606 1910 AGTATCTATTATAATGGAAACACCTACTACAACCCGT CCCTCCAGAGT 351 5607 1911 AREGPNWELLNAFDI 351 5608 1912 GCGAGAGAGGGGCCTAATTGGGAATTGTTGAATGCTT TCGATATC 351 5609 1913 TCCTATGAGCTGACTCAGCCACCCTCGGTGTCAGTGG CCCCAGGACAGACGGCCAGGATTACCTGTGGGGGAA ACAACATTGGAAGTAAAAATGTGCACTGGTACCAGCA GAAGCCAGGCCAGGCCCCTGTCTTGGTCGTCTATGAG GATACCCACCGGCCCTCAGGGATCCCTGAGCGATTCT CTGGCTCCAACTCTGGGAACACGGCCACCCTGACCAT CAGTAGGGTCGAAGCCGGGGATGAGGCCGACTATTAC TGTCAGGTGTGGGATACTAGTAGTGATCATGTGGTAT TCGGCGGAGGGACCAAGCTGACCGTCCTC 351 5610 1914 SYELTQPPSVSVAPGQTARITCGGNNIGSKNVHWYQQKP GQAPVLVVYEDTHRPSGIPERFSGSNSGNTATLTISRVEA GDEADYYCQVWDTSSDHVVFGGGTKLTVL 351 5611 1915 GGNNIGSKNVH 351 5612 1916 GGGGGAAACAACATTGGAAGTAAAAATGTGCAC 351 5613 1917 EDTHRPS 351 5614 1918 GAGGATACCCACCGGCCCTCA 351 5615 1919 QVWDTSSDHVV 351 5616 1920 CAGGTGTGGGATACTAGTAGTGATCATGTGGTA 352 5617 1921 CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGACTTC TGGTTACACCTTTAGTCATTTCGGTGTCACCTGGATAC GACAGGCCCCAGGACAAGGGCTTGAGTGGCTGGGAT GGATCAGCGCTTACAATGGTAACACAGACTCTGCAGA CAAACTGCAGGGCAGACTCACCATGACGACAGACAC ATCCACGAACACCGCCTACATGGAGTTGAGGAGCCTC AGATCTGACGACACGGCCGTCTATTACTGTGCGAGAG ATCCCCCCGCATCAGCTGCTGCCATGCTTGACTACTGG GGCCAGGGAACCCTGGTCACCGTCTCCTCA 352 5618 1922 QVQLVQSGAEVKKPGASVKVSCKTSGYTFSHFGVTWIR QAPGQGLEWLGWISAYNGNTDSADKLQGRLTMTTDTS TNTAYMELRSLRSDDTAVYYCARDPPASAAAMLDYWG QGTLVTVSS 352 5619 1923 YTFSHFGVT 352 5620 1924 TACACCTTTAGTCATTTCGGTGTCACC 352 5621 1925 WISAYNGNTDSADKLQG 352 5622 1926 TGGATCAGCGCTTACAATGGTAACACAGACTCTGCAG ACAAACTGCAGGGC 352 5623 1927 ARDPPASAAAMLDY 352 5624 1928 GCGAGAGATCCCCCCGCATCAGCTGCTGCCATGCTTG ACTAC 352 5625 1929 GACATCCAGATGACCCAGTCTCCACTCTCCCTGGCCGT CACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTA GTCAAGGCCTCGAATACACTGATGGAAACACCTACTT GAGTTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGG CGCCTCATTTATAAGGTTTCTAATCGGGACTCTGGGGT CCCAGACAGATTCAGCGGCAGCGGGGCAGGCACTGAT TTCACACTGAGAATCAGCAGGGTGGAGGCTGAGGATG TTGGGGTTTATTACTGCATGCAAGGTACACACGGGCG GGGAATCTCTTTCGGTCCTGGGACCAAAGTGGATATC AAA 352 5626 1930 DIQMTQSPLSLAVTLGQPASISCRSSQGLEYTDGNTYLS WFQQRPGQSPRRLIYKVSNRDSGVPDRFSGSGAGTDFTL RISRVEAEDVGVYYCMQGTHGRGISFGPGTKVDIK 352 5627 1931 RSSQGLEYTDGNTYLS 352 5628 1932 AGGTCTAGTCAAGGCCTCGAATACACTGATGGAAACA CCTACTTGAGT 352 5629 1933 KVSNRDS 352 5630 1934 AAGGTTTCTAATCGGGACTCT 352 5631 1935 MQGTHGRGIS 352 5632 1936 ATGCAAGGTACACACGGGCGGGGAATCTCT 353 5633 1937 CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAGGGTCTCCTGCAAGGCCTC TGGATACACCTTCACCGACTACTTTATGAACTGGGTGC GACAGGCCCCTGGAGGGGGCCTTGAGTGGATGGGGTG GATCAATCCTCTCAGTGGAGTCACAAAATATGCACAG CAGTTTCAGGGCAGTGTCACCATGACCACTGACACGT CCATCACCACAGGCTACATGGAGCTGAGGAGCCTGAG AGTTGACGACACGGCCGTCTATTATTGTGCGAGCCAG TCTTCCCCTTACACCCCGGGCGCCATGGGCGTCTGGG GCCAAGGGACCACGGTCACCGTCTCCTCA 353 5634 1938 QVQLVQSGAEVKKPGASVRVSCKASGYTFTDYFMNWV RQAPGGGLEWMGWINPLSGVTKYAQQFQGSVTMTTDT SITTGYMELRSLRVDDTAVYYCASQSSPYTPGAMGVWG QGTTVTVSS 353 5635 1939 YTFTDYFMN 353 5636 1940 TACACCTTCACCGACTACTTTATGAAC 353 5637 1941 WINPLSGVTKYAQQFQG 353 5638 1942 TGGATCAATCCTCTCAGTGGAGTCACAAAATATGCAC AGCAGTTTCAGGGC 353 5639 1943 ASQSSPYTPGAMGV 353 5640 1944 GCGAGCCAGTCTTCCCCTTACACCCCGGGCGCCATGG GCGTC 353 5641 1945 GACATCCGGATGACCCAGTCTCCATCCTCCCTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACTTGCCGGACA AGTCAGAGCGTTAGCGGCTATTTAAGTTGGTATCAGC AGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGC GGCATCCAATTTGTACAGTGGGGTCCCATCAAGGTTC AGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCA TCACCAGTCTGCAACCTGAAGATTTTGCAACTTACTTC TGTCAACTGAATTCCGGTGCCCTATTCACTTTCGGCCC TGGGACCAAGGTGGAAATCAAA 353 5642 1946 DIRMTQSPSSLSASVGDRVTITCRTSQSVSGYLSWYQQK PGKAPKLLIYAASNLYSGVPSRFSGSGSGTDFTLTITSLQP EDFATYFCQLNSGALFTFGPGTKVEIK 353 5643 1947 RTSQSVSGYLS 353 5644 1948 CGGACAAGTCAGAGCGTTAGCGGCTATTTAAGT 353 5645 1949 AASNLYS 353 5646 1950 GCGGCATCCAATTTGTACAGT 353 5647 1951 QLNSGALFT 353 5648 1952 CAACTGAATTCCGGTGCCCTATTCACT 354 5649 1953 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCA AGCCTGGAGAGTCCGTGAAACTCTCCTGCGCAGCGTC TGGATTCACCATCACTGACTCCTACATGGCCTGGATCC GCCAGTCTCCAGGGAAGGGGCTGGAGTGGCTTGCTTA CATTAGTAGTACTAGTCTTTTCACAGACTACACAGACT CTGTGAAGGGCCGATTCATCATCACCAGAGACAATGC CGAGAACTCACTCTATCTGCAAATGACCAGCCTGACA CCGGCAGACACGGGTGTCTATTTCTGTGCGAGGGCCA AAACATCCTACTACTTCTACGCTCTGGACGTCTGGGGC CCAGGCACCCTGGTCACCGTCTCCTCA 354 5650 1954 EVQLVESGGGLVKPGESVKLSCAASGFTITDSYMAWIRQ SPGKGLEWLAYISSTSLFTDYTDSVKGRFIITRDNAENSL YLQMTSLTPADTGVYFCARAKTSYYFYALDVWGPGTL VTVSS 354 5651 1955 FTITDSYMA 354 5652 1956 TTCACCATCACTGACTCCTACATGGCC 354 5653 1957 YISSTSLFTDYTDSVKG 354 5654 1958 TACATTAGTAGTACTAGTCTTTTCACAGACTACACAGA CTCTGTGAAGGGC 354 5655 1959 ARAKTSYYFYALDV 354 5656 1960 GCGAGGGCCAAAACATCCTACTACTTCTACGCTCTGG ACGTC 354 5657 1961 GAAACGACACTCACGCAGTCTCCAGGCACGCTGTCTT TGTCTCCGGGGGAAAGAGCCACCCTCTCCTGCAGGGC CAGTCAGAGTGTTAACAACAACTATCTAGCCTGGTTC CAGCACAAACCTGGCCAGGCTCCCAGACTCCTCATCT ATAATGCATCCAACAGGGCCGCTGGCATCCCAGACAG GTTCAGTGGTAGTGGGTCTGGGACAGACTTCACTCTC ACCATCAGCAAACTGGAGCCTGGAGATTCTGCAGTGT ATTACTGTCAGCGATATGGGAACTCTTGGCCGTTCGG CCAAGGGACCAAGGTGGAAATCAAA 354 5658 1962 ETTLTQSPGTLSLSPGERATLSCRASQSVNNNYLAWFQH KPGQAPRLLIYNASNRAAGIPDRFSGSGSGTDFTLTISKL EPGDSAVYYCQRYGNSWPFGQGTKVEIK 354 5659 1963 RASQSVNNNYLA 354 5660 1964 AGGGCCAGTCAGAGTGTTAACAACAACTATCTAGCC 354 5661 1965 NASNRAA 354 5662 1966 AATGCATCCAACAGGGCCGCT 354 5663 1967 QRYGNSWP 354 5664 1968 CAGCGATATGGGAACTCTTGGCCG 355 5665 1969 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCTTGGTAC AGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTC TGGATTCACCTTTAGTCAGTCTCCCATGAGCTGGGTCC GCCAGGCTCCTGGGAAGGGGCTGGAGTGGGTCTCCGG TATTAGTACTGGAGGGACCAATACATACTACGCAGAC TCCGTGAAGGGCCGCTTCACCATCTCCAGAGACAATT CCAAGAACACGTTGTATCTGCAAATGACCAGCCTGAG AGTCGGGGACACGGCCGTGTATTACTGTGCGAAAGAG AGTTTAGACTTTGGTTCAGGGAGCTACAACTGGTTCG ACACCTGGGGCCAGGGAACCCTGGTCACTGTCTCCTC A 355 5666 1970 QVQLVQSGGGLVQPGGSLRLSCAASGFTFSQSPMSWVR QAPGKGLEWVSGISTGGTNTYYADSVKGRFTISRDNSKN TLYLQMTSLRVGDTAVYYCAKESLDFGSGSYNWFDTW GQGTLVTVSS 355 5667 1971 FTFSQSPMS 355 5668 1972 TTCACCTTTAGTCAGTCTCCCATGAGC 355 5669 1973 GISTGGTNTYYADSVKG 355 5670 1974 GGTATTAGTACTGGAGGGACCAATACATACTACGCAG ACTCCGTGAAGGGC 355 5671 1975 AKESLDFGSGSYNWFDT 355 5672 1976 GCGAAAGAGAGTTTAGACTTTGGTTCAGGGAGCTACA ACTGGTTCGACACC 355 5673 1977 GAAATTGTATTGACGCAGTCTCCAGACTCCCTGGCTGT GTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCC AGCCAGAGTGTTTTATACAGGTCCAACAATAAGAACT ACTTAGCTTGGTACCAGCAGAGACCAGGACAGCCTCC TAGGCTGCTCATTTCCTGGGCATCTACCCGGGAATCCG GGGTCCCTGACCGATTCACTGGCAGCGGGTCTGGGAC AGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAA GATGTGGCAGTTTATTACTGTCACCAATATTATGATAC CCACACTTTTGGCCAGGGGACCAAAGTGGATATCAAA 355 5674 1978 EIVLTQSPDSLAVSLGERATINCKSSQSVLYRSNNKNYLA WYQQRPGQPPRLLISWASTRESGVPDRFTGSGSGTDFTL TISSLQAEDVAVYYCHQYYDTHTFGQGTKVDIK 355 5675 1979 KSSQSVLYRSNNKNYLA 355 5676 1980 AAGTCCAGCCAGAGTGTTTTATACAGGTCCAACAATA AGAACTACTTAGCT 355 5677 1981 WASTRES 355 5678 1982 TGGGCATCTACCCGGGAATCC 355 5679 1983 HQYYDTHT 355 5680 1984 CACCAATATTATGATACCCACACT 356 5681 1985 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCC AGCCTGGGAGGTCCCTGAGACTCTCCTGTGTAGCCTCT GGATTCAGCTTCAGTGCCTATGGCATGCACTGGGTTC GCCAGGTTCCAACCAAGGGGCTGGAGTGGGTGGCTGT TATATCATATGATGGAAGAGATATATACTATACAGAC TCCGTGAAGGGCCGATTCACCATTTCCAGAGACAATT CCAAGAACATGTTGTATCTGCAAATGAACAGCCTGAG ACCTGAGGACAGGGCTGTCTATTACTGTGCGAGAGAT CCGTCCCTCGGTTATAATAATCACTACTTTGACTATTG GGGCCAGGGAACCCTGGTCACCGTCTCTTCA 356 5682 1986 EVQLVESGGGVVQPGRSLRLSCVASGFSFSAYGMHWVR QVPTKGLEWVAVISYDGRDIYYTDSVKGRFTISRDNSKN MLYLQMNSLRPEDRAVYYCARDPSLGYNNHYFDYWGQ GTLVTVSS 356 5683 1987 FSFSAYGMH 356 5684 1988 TTCAGCTTCAGTGCCTATGGCATGCAC 356 5685 1989 VISYDGRDIYYTDSVKG 356 5686 1990 GTTATATCATATGATGGAAGAGATATATACTATACAG ACTCCGTGAAGGGC 356 5687 1991 ARDPSLGYNNHYFDY 356 5688 1992 GCGAGAGATCCGTCCCTCGGTTATAATAATCACTACTT TGACTAT 356 5689 1993 GAAATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTTT GTCTCCAGGGGAAACAGCCACCCTCTCCTGCAGGGCC AGTCAGAGTGTTACCGGCAACTTAGCCTGGTACCAAC AGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGC TGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTC AGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCA TCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTTC TGTCAGCAGCGTAGCAACTGGCCTCCTATGTACAGTTT TGGCCAGGGGACCAAGCTGGAGATCAAA 356 5690 1994 EIVLTQSPATLSLSPGETATLSCRASQSVTGNLAWYQQK PGQAPRLLIYAASNRATGIPARFSGSGSGTDFTLTISSLEP EDFAVYFCQQRSNWPPMYSFGQGTKLEIK 356 5691 1995 RASQSVTGNLA 356 5692 1996 AGGGCCAGTCAGAGTGTTACCGGCAACTTAGCC 356 5693 1997 AASNRAT 356 5694 1998 GCTGCATCCAACAGGGCCACT 356 5695 1999 QQRSNWPPMYS 356 5696 2000 CAGCAGCGTAGCAACTGGCCTCCTATGTACAGT 357 5697 2001 CAGGTCCAGCTTGTACAGTCTGGGGCTGAGGTGAAGA GGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCCTC TGGAGGCACCTTCAGAGGCTACCATATCAGCTGGGTG CGACAGGCCCCTGGACAAGGGCTCGAGTGGATGGGA GGGATCATCCATCTATTTGGGACAGTAAGCTACGCTC CGAAGTTCCAGGGCAGAGTCACGATCACCGCGGACGC ATCCACGGGCACAGCCCATATGGAGTTGAGCAGCCTG ACATCTGACGACACGGCCATATACTATTGTGCGAGAG ATGCTTACGAAGTCTGGACGGGTTCTTATCTCCCCCCT TTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCT CCTCA 357 5698 2002 QVQLVQSGAEVKRPGSSVKVSCKASGGTFRGYHISWVR QAPGQGLEWMGGIIHLFGTVSYAPKFQGRVTITADASTG TAHMELSSLTSDDTAIYYCARDAYEVWTGSYLPPFDYW GQGTLVTVSS 357 5699 2003 GTFRGYHIS 357 5700 2004 GGCACCTTCAGAGGCTACCATATCAGC 357 5701 2005 GIIHLFGTVSYAPKFQG 357 5702 2006 GGGATCATCCATCTATTTGGGACAGTAAGCTACGCTC CGAAGTTCCAGGGC 357 5703 2007 ARDAYEVWTGSYLPPFDY 357 5704 2008 GCGAGAGATGCTTACGAAGTCTGGACGGGTTCTTATC TCCCCCCTTTTGACTAC 357 5705 2009 GATATTGTGATGACTCAGACTCCAGGCACCCTGTCTTT GTCTCCCGGGGAAAGAGTCACCCTCTCCTGCAGGGCC AGTCAGACTGTTACAAGCAGCTACTTAGCCTGGTACC AGCAGAAACCTGGCCAGGCTCCCAGACTCCTCATCTA TGGTGCATTCACCAGGGCCACTGGCATCCCAGACAGG TTCAGTGGTAGTGGGTCTGGGACAGACTTCACTCTCA CCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTATA TTACTGTCAGCAGTATGGTAGCTCATTCCTCACTTTCG GCGGAGGGACCAAGCTGGAGATCAAA 357 5706 2010 DIVMTQTPGTLSLSPGERVTLSCRASQTVTSSYLAWYQQ KPGQAPRLLIYGAFTRATGIPDRFSGSGSGTDFTLTISRLE PEDFAVYYCQQYGSSFLTFGGGTKLEIK 357 5707 2011 RASQTVTSSYLA 357 5708 2012 AGGGCCAGTCAGACTGTTACAAGCAGCTACTTAGCC 357 5709 2013 GAFTRAT 357 5710 2014 GGTGCATTCACCAGGGCCACT 357 5711 2015 QQYGSSFLT 357 5712 2016 CAGCAGTATGGTAGCTCATTCCTCACT 358 5713 2017 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCA AGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTC TGGATTCACCTTCAGTAGCTATAGCATGAACTGGGTC CGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTAGTAGTAGTAGTAGTTACATATACTACGCAGA CTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAAC GCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGA GAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGA TGTGCAATATAGTGGCTACGATTCTGGGTACTACTTTG ACTACTGGGGCCAGGGAACCCTGGTCACTGTCTCCTC A 358 5714 2018 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVR QAPGKGLEWVSSISSSSSYIYYADSVKGRFTISRDNAKNS LYLQMNSLRAEDTAVYYCARDVQYSGYDSGYYFDYW GQGTLVTVSS 358 5715 2019 FTFSSYSMN 358 5716 2020 TTCACCTTCAGTAGCTATAGCATGAAC 358 5717 2021 SISSSSSYIYYADSVKG 358 5718 2022 TCCATTAGTAGTAGTAGTAGTTACATATACTACGCAG ACTCAGTGAAGGGC 358 5719 2023 ARDVQYSGYDSGYYFDY 358 5720 2024 GCGAGAGATGTGCAATATAGTGGCTACGATTCTGGGT ACTACTTTGACTAC 358 5721 2025 CAGCCTGTGCTGACTCAGCCACCCTCAGTGTCTGGGG CCCCAGGACAGAGGGTCACCATCTCCTGCACTGGGAG CAGCTCCAACATCGGGGCAGGTTATGATGTACACTGG TACCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTCA TCTATGGTAACAGCAATCGGCCCTCAGGGGTCCCTGA CCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCC TGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGA TTATTACTGCCAGTCCTATGACAGCAGCCTGAGTGCCC TTTATGTCTTCGGAACTGGGACCAAGGTGACCGTCCT A 358 5722 2026 QPVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSSLSALYVFGTGTKVTVL 358 5723 2027 TGSSSNIGAGYDVH 358 5724 2028 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATG TACAC 358 5725 2029 GNSNRPS 358 5726 2030 GGTAACAGCAATCGGCCCTCA 358 5727 2031 QSYDSSLSALYV 358 5728 2032 CAGTCCTATGACAGCAGCCTGAGTGCCCTTTATGTC 359 5729 2033 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCC AGCCGGGGGGGTCCCTGAGACTCTCCTGTGCAGGCTC TGGATTCGCCTTCGGTAGCTTCGCGATGCACTGGGTCC GTCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCTGT TATTTCATTTGACGGAAAGAATACAAAATATGCTGAC TCCGTGAAGGGCCGATTCACCACCTCCAGAGACAATT CCAGGAACACGCTCTATCTCCAAATGGACAGCCTGAG AGGTGACGACACGGCTATATATTACTGCGCGACAATT AGGGGAATTGTGGCTGGCCTTTGTGACAACTGGGGCC AGGGAACCCTGGTCACCGTCTCCTCA 359 5730 2034 EVQLVESGGGVVQPGGSLRLSCAGSGFAFGSFAMHWVR QAPGKGLEWVAVISFDGKNTKYADSVKGRFTTSRDNSR NTLYLQMDSLRGDDTAIYYCATIRGIVAGLCDNWGQGT LVTVSS 359 5731 2035 FAFGSFAMH 359 5732 2036 TTCGCCTTCGGTAGCTTCGCGATGCAC 359 5733 2037 VISFDGKNTKYADSVKG 359 5734 2038 GTTATTTCATTTGACGGAAAGAATACAAAATATGCTG ACTCCGTGAAGGGC 359 5735 2039 ATIRGIVAGLCDN 359 5736 2040 GCGACAATTAGGGGAATTGTGGCTGGCCTTTGTGACA AC 359 5737 2041 CAGCCTGTGCTGACTCAATCATCGTCTGACTCTGCTTC CCTGGGAGCCTCGGTCAAGCTCACCTGTACTCTGAGC AGTGGCCACAGAAACTACATCATCGCATGGCATCAAC AACAACCAGGGAAGGCCCCTCGGTTCCTGATGAAGGT TGAAGGTAGTGGAAGCTTCACCATGGGGAGCGGAGTT CCTGATCGCTTCTCGGGCTCCAGCTCTGGGGCTGACCG CTACCTCACCATCTCCAACCTCCAGTCTGAGGATGAG GCTGATTATTACTGTGAGGCCTGGGACTTTAACACGG GGGGGGTCTTCGGCGGAGGCACCCAGCTGACCGTCCT C 359 5738 2042 QPVLTQSSSDSASLGASVKLTCTLSSGHRNYIIAWHQQQ PGKAPRFLMKVEGSGSFTMGSGVPDRFSGSSSGADRYLT ISNLQSEDEADYYCEAWDFNTGGVFGGGTQLTVL 359 5739 2043 TLSSGHRNYIIA 359 5740 2044 ACTCTGAGCAGTGGCCACAGAAACTACATCATCGCA 359 5741 2045 VEGSGSFTMGS 359 5742 2046 GTTGAAGGTAGTGGAAGCTTCACCATGGGGAGC 359 5743 2047 EAWDFNTGGV 359 5744 2048 GAGGCCTGGGACTTTAACACGGGGGGGGTC 360 5745 2049 GAGGTGCAGCTGGTGGAGTCGGGCCCAGGACTGGTGA AGCCTTCGGGGACCCTGTCCCTCACCTGCGCTGTCTCT GGTGACTCCATCGTCGGTAGTGACTGGTGGAGTTGGA TCCGCCAGCCCCCCGGGAAGGGGCTGGAGTGGATTGG AGATATCTATCATGGTGGGACCACCAGCTACAACCCG TCCCTTAAGAGTCGAGTCACCATGTCAGTAGACAAGT CCAAGAACCAATTCTCCCTGAAGCTGACCTCTGTCAC CGCCGCGGACACAGCCGTGTATTACTGTGCGAGACTC TCGGGAAATTGTAGTGGTGGTAGCTGTTACTCGCCCTT TGACCACTGGGGCCAGGGAACCCTGGTCACCGTCTCT TCA 360 5746 2050 EVQLVESGPGLVKPSGTLSLTCAVSGDSIVGSDWWSWIR QPPGKGLEWIGDIYHGGTTSYNPSLKSRVTMSVDKSKN QFSLKLTSVTAADTAVYYCARLSGNCSGGSCYSPFDHW GQGTLVTVSS 360 5747 2051 DSIVGSDWWS 360 5748 2052 GACTCCATCGTCGGTAGTGACTGGTGGAGT 360 5749 2053 DIYHGGTTSYNPSLKS 360 5750 2054 GATATCTATCATGGTGGGACCACCAGCTACAACCCGT CCCTTAAGAGT 360 5751 2055 ARLSGNCSGGSCYSPFDH 360 5752 2056 GCGAGACTCTCGGGAAATTGTAGTGGTGGTAGCTGTT ACTCGCCCTTTGACCAC 360 5753 2057 GACATCCAGATGACCCAGTCTCCATCCTCCTTGTCTGC ATCTGTGGGAGACAGAGTCACCATCACTTGCCGGGCA AGTCAGACCATTAATGGTTATTTAAATTGGTATCAAC AAAGACCAGGGAAAGCCCCTAAACTCCTGATCTCTGC TGCATCCAGTTTGCAGAGTGGGGTCCCATCAAGGTTC CGTGGCAGTGGATATGGGACAGATTTCACTCTCACCA TCAGCAGTCTGCAACCTGAAGATTTTGCAACTTATTTC TGTCAACAGAGTTACAATACTGTGTACACTTTTGGGC AGGGGACCAAAGTGGATATCAAA 360 5754 2058 DIQMTQSPSSLSASVGDRVTITCRASQTINGYLNWYQQR PGKAPKLLISAASSLQSGVPSRFRGSGYGTDFTLTISSLQP EDFATYFCQQSYNTVYTFGQGTKVDIK 360 5755 2059 RASQTINGYLN 360 5756 2060 CGGGCAAGTCAGACCATTAATGGTTATTTAAAT 360 5757 2061 AASSLQS 360 5758 2062 GCTGCATCCAGTTTGCAGAGT 360 5759 2063 QQSYNTVYT 360 5760 2064 CAACAGAGTTACAATACTGTGTACACT 361 5761 2065 CAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAA AAGCCCGGGGAGTCTCTGAAGATCTCCTGTAAGGGTT CTGGATACAGCTTTAGCAGCTACTGGATCGGCTGGGT GCGCCAGATGCCCGGGAAAGGCCTGGAGTGGATGGG GATCATCTATCCTGGTGACTCTGATACCAGATACAGC CCGTCGCTCCAAGGCCAGGTCACCATCTCAGGCGACA AGTCCATCAGTACCGCCTTCCTGCAGTGGAGCAGCCT GAAGGCCTCGGACACCGCCATGTATTACTGTGCGAGA CCCATGACTACCCAAGAAGGTTTTGATTTGTGGGGCC AAGGGACAATGGTCACCGTCTCTTCA 361 5762 2066 QVQLVQSGAEVKKPGESLKISCKGSGYSFSSYWIGWVR QMPGKGLEWMGIIYPGDSDTRYSPSLQGQVTISGDKSIST AFLQWSSLKASDTAMYYCARPMTTQEGFDLWGQGTMV TVSS 361 5763 2067 YSFSSYWIG 361 5764 2068 TACAGCTTTAGCAGCTACTGGATCGGC 361 5765 2069 IIYPGDSDTRYSPSLQG 361 5766 2070 ATCATCTATCCTGGTGACTCTGATACCAGATACAGCCC GTCGCTCCAAGGC 361 5767 2071 ARPMTTQEGFDL 361 5768 2072 GCGAGACCCATGACTACCCAAGAAGGTTTTGATTTG 361 5769 2073 GACATCCGGTTGACCCAGTCTCCATCTTCTGTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCG AGTCAGGGTATTAGCGACTGGTTAGCCTGGTATCAGC AGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATGC TGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTC AGCGGCAGTGGATCTGGGACAGATTTCACTCTCACTA TCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTAT TGTCAACAGACTAACAGTTTCCTCCCGCTCACTTTCGG CGGAGGGACCAAAGTGGATATCAAA 361 5770 2074 DIRLTQSPSSVSASVGDRVTITCRASQGISDWLAWYQQK PGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCQQTNSFLPLTFGGGTKVDIK 361 5771 2075 RASQGISDWLA 361 5772 2076 CGGGCGAGTCAGGGTATTAGCGACTGGTTAGCC 361 5773 2077 AASSLQS 361 5774 2078 GCTGCATCCAGTTTGCAAAGT 361 5775 2079 QQTNSFLPLT 361 5776 2080 CAACAGACTAACAGTTTCCTCCCGCTCACT 362 5777 2081 GAGGTGCAGCTGGTGGAGTCGGGCCCCCGACTGGTGA AGCCTTCACAGACCCTGTCCCTCACCTGCACCGTCTAT GGTGGCTCCATCAGCGGTGGTCAAAACTACTACAGTT GGGTCCGCCAGCCCCCAGGGAAGGGCCTGGAGTGGAT TGGGTACATCTTTTCCAGTGGGACCACCTACTACAAG CCGTCCCTCAAGAGTCGAATTTCCATTTCATTTGACAC GTCCAAGAACCAGTTCTCCCTGAACCTGGCCTCTGTG ACGGCCGCAGACACGGCCGTATATTTCTGTGCCAGAT CCGCTGACATTGATATCGTTTGGGGGAGTTCTCTCTAC ATGCCTCTCTGGGGCCAGGGAACCCTGGTCACCGTCT CCTCA 362 5778 2082 EVQLVESGPRLVKPSQTLSLTCTVYGGSISGGQNYYSWV RQPPGKGLEWIGYIFSSGTTYYKPSLKSRISISFDTSKNQF SLNLASVTAADTAVYFCARSADIDIVWGSSLYMPLWGQ GTLVTVSS 362 5779 2083 GSISGGQNYYS 362 5780 2084 GGCTCCATCAGCGGTGGTCAAAACTACTACAGT 362 5781 2085 YIFSSGTTYYKPSLKS 362 5782 2086 TACATCTTTTCCAGTGGGACCACCTACTACAAGCCGTC CCTCAAGAGT 362 5783 2087 ARSADIDIVWGSSLYMPL 362 5784 2088 GCCAGATCCGCTGACATTGATATCGTTTGGGGGAGTT CTCTCTACATGCCTCTC 362 5785 2089 GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTT GTCTCCAGGACAAAGAGCCACCCTCTCCTGCAGGGCC ACTCACATTGTCAGTAACAGCTACTTAGCCTGGTACC AGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCCA TGGTGTTTCCATCAGGGCCACTGGCATCCCAGACAGG TTCTCTGGCAGTGGGTCTGGGACAGACTTCACTCTCAC CATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTAT TTCTGTCAGCAGTATGGTACCTCACCGTGGACGTTCGG CCAAGGGACCAAGCTGGAGATCAAA 362 5786 2090 EIVLTQSPGTLSLSPGQRATLSCRATHIVSNSYLAWYQQ KPGQAPRLLIHGVSIRATGIPDRFSGSGSGTDFTLTISRLE PEDFAVYFCQQYGTSPWTFGQGTKLEIK 362 5787 2091 RATHIVSNSYLA 362 5788 2092 AGGGCCACTCACATTGTCAGTAACAGCTACTTAGCC 362 5789 2093 GVSIRAT 362 5790 2094 GGTGTTTCCATCAGGGCCACT 362 5791 2095 QQYGTSPWT 362 5792 2096 CAGCAGTATGGTACCTCACCGTGGACG 363 5793 2097 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCA AGCCGGGGGGGTCCCTGAGACTCTCCTGTGTAGCCTC TGGATTTACCTTCAGCAGTTATGCCATGAATTGGGTCC GCCAGGCTCCAGGGAAGGGGCTGGACTGGGTCTCCTC TATCAGTGCTGGTAGCAATTTCATAGACGACGCAGAC TCAGTGAAGGGCCGCTTCACCATCTCCAGAGACAACG CCAGGAACTCACTGTTTCTGCAGATGAACAGCCTGAG AGCCGAGGACACGGCTGTGTATTACTGTGCGAGAATT GGGTACAGTAGCGCGCACCACTACCAGTACTACATGG ACGTCTGGGGCACGGGGACCACGGTCACCGTCTCCTC A 363 5794 2098 QVQLVESGGGLVKPGGSLRLSCVASGFTFSSYAMNWVR QAPGKGLDWVSSISAGSNFIDDADSVKGRFTISRDNARN SLFLQMNSLRAEDTAVYYCARIGYSSAHHYQYYMDVW GTGTTVTVSS 363 5795 2099 FTFSSYAMN 363 5796 2100 TTTACCTTCAGCAGTTATGCCATGAAT 363 5797 2101 SISAGSNFIDDADSVKG 363 5798 2102 TCTATCAGTGCTGGTAGCAATTTCATAGACGACGCAG ACTCAGTGAAGGGC 363 5799 2103 ARIGYSSAHHYQYYMDV 363 5800 2104 GCGAGAATTGGGTACAGTAGCGCGCACCACTACCAGT ACTACATGGACGTC 363 5801 2105 CAGTCTGTCCTGACGCAGCCGCCCTCAGTGTCTGGGG CCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGCAG CAGCTCCAACATCGGGGCAGGTTATGATGTCCACTGG TACCAGGATCTTCCAGGAACTGCCCCCAAACTCCTCA TCTATGGTAACACCAATCGGCCCTCAGGGGTCCCTGA CCGATTCTCTGGCTCCAAGTCTGGCGCCTCAGCCTCCC TGGTCATCACTGGGCTCCAGGCTGAGGATGAGGCTGA TTATTACTGCCAGTCCTATGACAAGAGCCTGAGTGGT GGGTATGTCTTCGGAACTGGGACCAAGGTCACCGTCC TA 363 5802 2106 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ DLPGTAPKLLIYGNTNRPSGVPDRFSGSKSGASASLVITG LQAEDEADYYCQSYDKSLSGGYVFGTGTKVTVL 363 5803 2107 TGSSSNIGAGYDVH 363 5804 2108 ACTGGCAGCAGCTCCAACATCGGGGCAGGTTATGATG TCCAC 363 5805 2109 GNTNRPS 363 5806 2110 GGTAACACCAATCGGCCCTCA 363 5807 2111 QSYDKSLSGGYV 363 5808 2112 CAGTCCTATGACAAGAGCCTGAGTGGTGGGTATGTC 364 5809 2113 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAGGGTCACCTGCAAGGCCTC TGGATACACCTTCACCGACTACTTTATGAACTGGGTGC GACAGGCCCCTGGAGGGGGCCTTGAGTGGATGGGGTG GATCAATCCTCTCAGTGGAGTCACAAAATATGCACAG CAGTTTCAGGGCAGTGTCACCATGACCACTGACACGT CCATCACCACAGGCTACATGGAGCTGAGGAGCCTGAG AGTTGACGACACGGCCGTCTATTATTGTGCGAGCCAG TCTTCCCCTTACACCCCGGGCGCCATGGGCGTCTGGG GCCAAGGGACCACGGTCACCGTCTCTTCA 364 5810 2114 QVQLVQSGAEVKKPGASVRVTCKASGYTFTDYFMNWV RQAPGGGLEWMGWINPLSGVTKYAQQFQGSVTMTTDT SITTGYMELRSLRVDDTAVYYCASQSSPYTPGAMGVWG QGTTVTVSS 364 5811 2115 YTFTDYFMN 364 5812 2116 TACACCTTCACCGACTACTTTATGAAC 364 5813 2117 WINPLSGVTKYAQQFQG 364 5814 2118 TGGATCAATCCTCTCAGTGGAGTCACAAAATATGCAC AGCAGTTTCAGGGC 364 5815 2119 ASQSSPYTPGAMGV 364 5816 2120 GCGAGCCAGTCTTCCCCTTACACCCCGGGCGCCATGG GCGTC 364 5817 2121 TCCTATGAGCTGATACAGCTACCCTCGGTGTCAGTGTC CCCAGGACAGACGGCCAGGATCACCTGCTCTGGAGAT GCATTGCCAAAGCAATATGCTTATTGGTACCAGCAGA AGCCAGGCCAGGCCCCTGTGCTGGTGATATATAAAGA CAGTGAGAGGCCCTCAGGGATCCCTGAGCGATTCTCT GGCTCCAGCTCAGGGACAACAGTCACGTTGACCATCA GTGGAGTCCAGGCAGAAGACGAGGCTGACTATTACTG TCAATCAGCAGACAGCAGTGGTACTTATCCGGTGGTG TTCGGCGGAGGGACCAAGCTCACCGTCCTA 364 5818 2122 SYELIQLPSVSVSPGQTARITCSGDALPKQYAYWYQQKP GQAPVLVIYKDSERPSGIPERFSGSSSGTTVTLTISGVQAE DEADYYCQSADSSGTYPVVFGGGTKLTVL 364 5819 2123 SGDALPKQYAY 364 5820 2124 TCTGGAGATGCATTGCCAAAGCAATATGCTTAT 364 5821 2125 KDSERPS 364 5822 2126 AAAGACAGTGAGAGGCCCTCA 364 5823 2127 QSADSSGTYPVV 364 5824 2128 CAATCAGCAGACAGCAGTGGTACTTATCCGGTGGTG 365 5825 2145 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCA (ADI- AGCCTGGGGGGGCCCTGAGACTCTCCTGTGCAGCCTC 31382) TGGATTCAGCTTCAGGAGCTATAGCATGAACTGGGTC CGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTAGTAGTAGTAGTAATTACATAAACTACGCAGA CTCAGTGAAGGGCCGATTCAGCATCTCCAGAGACAAC GCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGA GAGCCGAGGACACGGCTGTCTATTACTGTGCGAGAGA TTTGTTACCCGTCGAGCGGGGTCCCGCTTTTGATATCT GGGGCCAAGGGACAATGGTCACCGTCTCTTCA 5826 2146 EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVR QAPGKGLEWVSSISSSSNYINYADSVKGRFSISRDNAKNS LYLQMNSLRAEDTAVYYCARDLLPVERGPAFDIWGQGT MVTVSS 5827 2147 FSFRSYSMN 5828 2148 SISSSSNYINYADSVKG 5829 2149 ARDLLPVERGPAFDI 5830 2150 TCCTACGAGCTGACACAGCCACCCTCAGTGTCTGGGG CCCCAGGGCAGAGGGTCACTATCTCCTGCACTGGGAG CAGCTCCAACATCGGGAGGGGTTATGATGTACACTGG TTCCAGCAGCTTCCAGGAGCAGCCCCCAAACTCCTCA TCTATGCTAACAGCAATCGGCCCTCAGGGGTCCCTGA CCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCC TGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGA TTATTACTGCCAGTCCTATGACAGCAGACTGGGTGGTT CGGTATTCGGCGGAGGGACCAAGGTGACCGTCCTA 5831 2151 SYELTQPPSVSGAPGQRVTISCTGSSSNIGRGYDVHWFQ QLPGAAPKLLIYANSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSRLGGSVFGGGTKVTVL 5832 2152 TGSSSNIGRGYDVH 5833 2153 ANSNRPS 5834 2154 QSYDSRLGGSV 366 5835 2155 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCA (ADI- AGCCTGGGGGGGCCCTGAGACTCTCCTGTGCAGCCTC 31383) TGGATTCAGCTTCAGGAGCTATAGCATGAACTGGGTC CGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTAGTAGTAGTAGTAATTACATAAACTACGCAGA CTCAGTGAAGGGCCGATTCAGCATCTCCAGAGACAAC GCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGA GAGCCGAGGACACGGCTGTCTATTACTGTGCGAGAGA TTTGTTACCCGTCGAGCGGGGTCCCGCTTTTGATATCT GGGGCCAAGGGACAATGGTCACCGTCTCTTCA 5836 2156 EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVR QAPGKGLEWVSSISSSSNYINYADSVKGRFSISRDNAKNS LYLQMNSLRAEDTAVYYCARDLLPVERGPAFDIWGQGT MVTVSS 5837 2157 FSFRSYSMN 5838 2158 SISSSSNYINYADSVKG 5839 2159 ARDLLPVERGPAFDI 5840 2160 TCCTATGAGCTGACACAGCCACCCTCAGTGTCTGGGG CCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAG CAGCTCCAACATCGGGGCAGGTTATGATGTACACTGG TTCCAGCAGCTTCCAGGAGCAGCCCCCAAACTCCTCA TCTATCGTAACAGCAATCGGCCCTCAGGGGTCCCTGA CCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCC TGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGA TTATTACTGCCAGTCCTATGACAGCAGACTGGGTGGTT CGAATTTCGGCGGAGGGACCAAGGTGACCGTCCTA 5841 2161 SYELTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWFQ QLPGAAPKLLIYRNSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSRLGGSNFGGGTKVTVL 5842 2162 TGSSSNIGAGYDVH 5843 2163 RNSNRPS 5844 2164 QSYDSRLGGSN 367 5845 2165 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCA (ADI- AGCCTGGGGGGGCCCTGAGACTCTCCTGTGCAGCCTC 31384) TGGATTCAGCTTCAGGAGCTATAGCATGAACTGGGTC CGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTAGTGCTAGTAGTAATTACATAAACTACGCAGA CTCAGTGAAGGGCCGATTCAGCATCTCCAGAGACAAC GCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGA GAGCCGAGGACACGGCTGTCTATTACTGTGCGAGAGA TTTGTTACCCGTCGAGCGGGGTCCCGCTTTTGATATCT GGGGCCAAGGGACAATGGTCACCGTCTCTTCA 5846 2166 EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVR QAPGKGLEWVSSISASSNYINYADSVKGRFSISRDNAKN SLYLQMNSLRAEDTAVYYCARDLLPVERGPAFDIWGQG TMVTVSS 5847 2167 FSFRSYSMN 5848 2168 SISASSNYINYADSVKG 5849 2169 ARDLLPVERGPAFDI 5850 2170 TCCTATGAGCTGACACAGCCACCCTCAGTGTCTGGGG CCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAG CAGCTCCAACATCGGGGCAGGTTATGATGTACACTGG TTCCAGCAGCTTCCAGGAGCAGCCCCCAAACTCCTCA TCTATGCTAACAGCAATCGGCCCTCAGGGGTCCCTGA CCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCC TGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGA TTATTACTGCCAGTCCTATGACAGCAGACTGGGTGGTT CGGTATTCGGCGGAGGGACCAAGGTGACCGTCCTA 5851 2171 SYELTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWFQ QLPGAAPKLLIYANSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSRLGGSVFGGGTKVTVL 5852 2172 TGSSSNIGAGYDVH 5853 2173 ANSNRPS 5854 2174 QSYDSRLGGSV 368 5855 2175 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCA (ADI- AGCCTGGGGGGGCCCTGAGACTCTCCTGTGCAGCCTC 31385) TGGATTCAGCTTCAGGAGCTATAGCATGAACTGGGTC CGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTAGTAGTAGTAGTACTTACATAAACTACGCAGA CTCAGTGAAGGGCCGATTCAGCATCTCCAGAGACAAC GCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGA GAGCCGAGGACACGGCTGTCTATTACTGTGCGAGAGA TTTGAGTCCCGTCGAGCGGGGTCCCGCTTTTGATATCT GGGGCCAAGGGACAATGGTCACCGTCTCTTCA 5856 2176 EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVR QAPGKGLEWVSSISSSSTYINYADSVKGRFSISRDNAKNS LYLQMNSLRAEDTAVYYCARDLSPVERGPAFDIWGQGT MVTVSS 5857 2177 FSFRSYSMN 5858 2178 SISSSSTYINYADSVKG 5859 2179 ARDLSPVERGPAFDI 5860 2180 TCCTATGAGCTGACACAGCCACCCTCAGTGTCTGGGG CCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAG CAGCTCCAACATCGGGGCAGGTTATGATGTACACTGG TTCCAGCAGCTTCCAGGAGCAGCCCCCAAACTCCTCA TCTATGCTAACAGCAATCGGCCCTCAGGGGTCCCTGA CCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCC TGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGA TTATTACTGCCAGTCCTATGACAGCAGACTGGGTGGTT CGGTATTCGGCGGAGGGACCAAGGTGACCGTCCTA 5861 2181 SYELTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWFQ QLPGAAPKLLIYANSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSRLGGSVFGGGTKVTVL 5862 2182 TGSSSNIGAGYDVH 5863 2183 ANSNRPS 5864 2184 QSYDSRLGGSV 369 5865 2185 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCA (ADI- AGCCTGGGGGGGCCCTGAGACTCTCCTGTGCAGCCTC 31345) TGGATTCAGCTTCAGGAGCTATAGCATGAACTGGGTC CGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTAGTGCTAGTAGTAATTACATAAACTACGCAGA CTCAGTGAAGGGCCGATTCAGCATCTCCAGAGACAAC GCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGA GAGCCGAGGACACGGCTGTCTATTACTGTGCGAGAGA TTTGTTACCCGTCGAGCGGGGTCCCGCTTTTGATATCT GGGGCCAAGGGACAATGGTCACCGTCTCTTCA 5866 2186 EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVR QAPGKGLEWVSSISASSNYINYADSVKGRFSISRDNAKN SLYLQMNSLRAEDTAVYYCARDLLPVERGPAFDIWGQG TMVTVSS 5867 2187 FSFRSYSMN 5868 2188 SISASSNYINYADSVKG 5869 2189 ARDLLPVERGPAFDI 5870 2190 TCCTACGAGCTGACACAGCCACCCTCAGTGTCTGGGG CCCCAGGGCAGAGGGTCACTATCTCCTGCACTGGGAG CAGCTCCAACATCGGGAGGGGTTATGATGTACACTGG TTCCAGCAGCTTCCAGGAGCAGCCCCCAAACTCCTCA TCTATGCTAACAGCAATCGGCCCTCAGGGGTCCCTGA CCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCC TGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGA TTATTACTGCCAGTCCTATGACAGCAGACTGGGTGGTT CGGTATTCGGCGGAGGGACCAAGGTGACCGTCCTA 5871 2191 SYELTQPPSVSGAPGQRVTISCTGSSSNIGRGYDVHWFQ QLPGAAPKLLIYANSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSRLGGSVFGGGTKVTVL 5872 2192 TGSSSNIGRGYDVH 5873 2193 ANSNRPS 5874 2194 QSYDSRLGGSV 370 5875 2195 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCA (ADI- AGCCTGGGGGGGCCCTGAGACTCTCCTGTGCAGCCTC 31346) TGGATTCAGCTTCAGGAGCTATAGCATGAACTGGGTC CGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTAGTGCTAGTAGTAATTACATAAACTACGCAGA CTCAGTGAAGGGCCGATTCAGCATCTCCAGAGACAAC GCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGA GAGCCGAGGACACGGCTGTCTATTACTGTGCGAGAGA TTTGTTACCCGTCGAGCGGGGTCCCGCTTTTGATATCT GGGGCCAAGGGACAATGGTCACCGTCTCTTCA 5876 2196 EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVR QAPGKGLEWVSSISASSNYINYADSVKGRFSISRDNAKN SLYLQMNSLRAEDTAVYYCARDLLPVERGPAFDIWGQG TMVTVSS 5877 2197 FSFRSYSMN 5878 2198 SISASSNYINYADSVKG 5879 2199 ARDLLPVERGPAFDI 5880 2200 TCCTATGAGCTGACACAGCCACCCTCAGTGTCTGGGG CCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAG CAGCTCCAACATCGGGGCAGGTTATGATGTACACTGG TTCCAGCAGCTTCCAGGAGCAGCCCCCAAACTCCTCA TCTATCGTAACAGCAATCGGCCCTCAGGGGTCCCTGA CCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCC TGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGA TTATTACTGCCAGTCCTATGACAGCAGACTGGGTGGTT CGAATTTCGGCGGAGGGACCAAGGTGACCGTCCTA 5881 2201 SYELTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWFQ QLPGAAPKLLIYRNSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSRLGGSNFGGGTKVTVL 5882 2202 TGSSSNIGAGYDVH 5883 2203 RNSNRPS 5884 2204 QSYDSRLGGSN 371 5885 2205 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCA (ADI- AGCCTGGGGGGGCCCTGAGACTCTCCTGTGCAGCCTC 31354) TGGATTCAGCTTCAGGAGCTATAGCATGAACTGGGTC CGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTAGTAGTAGTAGTACTTACATAAACTACGCAGA CTCAGTGAAGGGCCGATTCAGCATCTCCAGAGACAAC GCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGA GAGCCGAGGACACGGCTGTCTATTACTGTGCGAGAGA TTTGAGTCCCGTCGAGCGGGGTCCCGCTTTTGATATCT GGGGCCAAGGGACAATGGTCACCGTCTCTTCA 5886 2206 EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVR QAPGKGLEWVSSISSSSTYINYADSVKGRFSISRDNAKNS LYLQMNSLRAEDTAVYYCARDLSPVERGPAFDIWGQGT MVTVSS 5887 2207 FSFRSYSMN 5888 2208 SISSSSTYINYADSVKG 5889 2209 ARDLSPVERGPAFDI 5890 2210 TCCTACGAGCTGACACAGCCACCCTCAGTGTCTGGGG CCCCAGGGCAGAGGGTCACTATCTCCTGCACTGGGAG CAGCTCCAACATCGGGAGGGGTTATGATGTACACTGG TTCCAGCAGCTTCCAGGAGCAGCCCCCAAACTCCTCA TCTATGCTAACAGCAATCGGCCCTCAGGGGTCCCTGA CCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCC TGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGA TTATTACTGCCAGTCCTATGACAGCAGACTGGGTGGTT CGGTATTCGGCGGAGGGACCAAGGTGACCGTCCTA 5891 2211 SYELTQPPSVSGAPGQRVTISCTGSSSNIGRGYDVHWFQ QLPGAAPKLLIYANSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSRLGGSVFGGGTKVTVL 5892 2212 TGSSSNIGRGYDVH 5893 2213 ANSNRPS 5894 2214 QSYDSRLGGSV 372 5895 2215 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCA (ADI- AGCCTGGGGGGGCCCTGAGACTCTCCTGTGCAGCCTC 31362) TGGATTCAGCTTCAGGAGCTATAGCATGAACTGGGTC CGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTAGTAGTAGTAGTACTTACATAAACTACGCAGA CTCAGTGAAGGGCCGATTCAGCATCTCCAGAGACAAC GCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGA GAGCCGAGGACACGGCTGTCTATTACTGTGCGAGAGA TTTGAGTCCCGTCGAGCGGGGTCCCGCTTTTGATATCT GGGGCCAAGGGACAATGGTCACCGTCTCTTCA 5896 2216 EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVR QAPGKGLEWVSSISSSSTYINYADSVKGRFSISRDNAKNS LYLQMNSLRAEDTAVYYCARDLSPVERGPAFDIWGQGT MVTVSS 5897 2217 FSFRSYSMN 5898 2218 SISSSSTYINYADSVKG 5899 2219 ARDLSPVERGPAFDI 5900 2220 TCCTATGAGCTGACACAGCCACCCTCAGTGTCTGGGG CCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAG CAGCTCCAACATCGGGGCAGGTTATGATGTACACTGG TTCCAGCAGCTTCCAGGAGCAGCCCCCAAACTCCTCA TCTATCGTAACAGCAATCGGCCCTCAGGGGTCCCTGA CCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCC TGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGA TTATTACTGCCAGTCCTATGACAGCAGACTGGGTGGTT CGAATTTCGGCGGAGGGACCAAGGTGACCGTCCTA 5901 2221 SYELTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWFQ QLPGAAPKLLIYRNSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSRLGGSNFGGGTKVTVL 5902 2222 TGSSSNIGAGYDVH 5903 2223 RNSNRPS 5904 2224 QSYDSRLGGSN

Additional Embodiments:

Embodiment 1. An isolated antibody or an antigen-binding fragment thereor that specifically binds to Respiratory Syncytial Virus (RSV) F protein (F), wherein at least one of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and CDRL3 amino acid sequence of the antibody or the antigen-binding fragment thereof is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to at least one the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences as disclosed in Table 6 of an antibody selected from Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; and wherein said antibody or the antigen-binding fragment thereof also has one or more of the following characteristics:

-   -   a) the antibody or antigen-binding fragment thereof         cross-competes with said antibody ar antigen-binding fragment         thereof for binding to RSV-F;     -   b) the antibody or antigen-binding fragment thereof displays         better binding affinity for the PreF form of RSV-F relative to         the PostF form;     -   c) the antibody or antigen-binding fragment thereof displays a         clean or low polyreactivity profile;     -   d) the antibody or antigen-binding fragment thereof displays         neutralization activity toward RSV subtype A and RSV subtype B         in vitro;     -   e) the antibody or antigen-binding fragment thereof displays         antigenic site specificity for RSV-F at Site Ø, Site I, Site II,         Site III, Site IV, or Site V;     -   f) the antibody or antigen-binding fragment thereof displays         antigenic site specificity for RSV-F Site Ø, Site V, or Site III         relative to RSV-F Site I, Site II, or Site IV;     -   g) at least a portion of the epitope with which the antibody or         antigen-binding fragment thereof interacts comprises the α3         helix and β3/β4 hairpin of PreF;     -   h) the antibody or antigen-binding fragment thereof displays an         in vitro neutralization potency (IC₅₀) of between about 0.5         microgram/milliliter (ug/ml) to about 5 ug/ml; between about         0.05 ug/ml to about 0.5 ug/ml; or less than about 0.05 mg/ml;     -   i) the binding affinity and/or epitopic specificity of the         antibody or antigen-binding fragment thereof for any one of the         RSV-F variants designated as 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG         in FIG. 7A is reduced or eliminated relative to the binding         affinity and/or epitopic specificity of said antibody or         antigen-binding fragment thereof for the RSV-F or RSV-F DS-Cav1;     -   j) the antibody or antigen-binding fragment thereof of displays         a cross-neutalization potency (IC₅₀) against human         metapneumovirus (HMPV);     -   k) the antibody or antigen-binding fragment thereof does not         complete with D25, MPE8, palivisumab, motavizumab, or AM-14; or     -   l) the antibody or antigen-binding fragment thereof displays at         least about 2-fold; at least about 3-fold; at least about         4-fold; at least about 5-fold; at least about 6-fold; at least         about 7-fold; at least about 8-fold; at least about 9-fold; at         least about 10-fold; at least about 15-fold; at least about         20-fold; at least about 25-fold; at least about 30-fold; at         least about 35-fold; at least about 40-fold; at least about         50-fold; at least about 55-fold; at least about 60-fold; at         least about 70-fold; at least about 80-fold; at least about         90-fold; at least about 100-fold; greater than about 100-fold;         and folds in between any of the foregoing; greater         neutralization potency (IC50) than D25 and/or palivizumab.

Embodiment 2. The isolated antibody or antigen-binding fragment thereof of Embodiment 1, wherein the antibody or antigen-binding fragment thereof comprises: at least two; at least three; at least 4; at least 5; at least 6; at least 7; at least 8; at least 9; at least 10; at least 11; or at least 12; of characteristics a) through l).

Embodiment 3. The isolated antibody or antigen-binding fragment thereof of Embodiment 1 or 2, wherein the antibody or antigen-binding fragment thereof comprises:

-   -   a) the CDRH3 amino acid sequence of any one of the antibodies         designated Antibody Number 232 through Antibody Number 372 as         disclosed in Table 6;     -   b) the CDRH2 amino acid sequence of any one of the antibodies         designated Antibody Number 232 through Antibody Number 372 as         disclosed in Table 6;     -   c) the CDRH1 amino acid sequence of any one of the antibodies         designated Antibody Number 232 through Antibody Number 372 as         disclosed in Table 6;     -   d) the CDRL3 amino acid sequence of any one of the antibodies         designated Antibody Number 232 through Antibody Number 372 as         disclosed in Table 6;     -   e) the CDRL2 amino acid sequence of any one of the antibodies         designated Antibody Number 232 through Antibody Number 372 as         disclosed in Table 6;     -   f) the CDRL1 amino acid sequence of any one of the antibodies         designated Antibody Number 232 through Antibody Number 372 as         disclosed in Table 6; or     -   g) any combination of two or more of a), b), c), d), e), and f).

Embodiment 4. The isolated antibody or antigen-binding fragment thereof of any one of Embodiments 1 through 3, wherein the antibody or antigen-binding fragment thereof comprises:

-   -   a) a heavy chain (HC) amino acid sequence of any one of the         antibodies designated Antibody Number 232 through Antibody         Number 372 as disclosed in Table 6; and/or     -   b) a light chain (LC) amino acid sequence of any one of the         antibodies designated Antibody Number 232 through Antibody         Number 372 as disclosed in Table 6.

Embodiment 5. The isolated antibody or antigen-binding fragment thereof of any one of Embodiments 1 through 4, wherein the antibody is selected from the group consisting antibodies that are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to any one of the antibodies designated as Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.

Embodiment 6. The isolated antibody or antigen-binding fragment thereof of any one of Embodiments 1 through 5, wherein the antibody is selected from the group consisting of the antibodies designated as Antibody 232 through Antibody Number 372 as disclosed in Table 6.

Embodiment 7. An isolated nucleic acid sequence encoding an antibody or antigen-binding fragment thereof according to any one of Embodiments 1 through 6.

Embodiment 8. An expression vector comprising the isolated nucleic acid sequence according to Embodiment 7.

Embodiment 9. A host cell transfected, transformed, or transduced with the nucleic acid sequence according to Embodiment 7 or the expression vector according to Embodiment 8.

Embodiment 10. A pharmaceutical composition comprising: one or more of the isolated antibodies or antigen-binding fragments thereof according to any one of Embodiments 1 through 6; and a pharmaceutically acceptable carrier and/or excipient.

Embodiment 11. A pharmaceutical composition comprising: one or more nucleic acid sequences according to Embodiment 7; or one or more the expression vectors according to Embodiment 8; and a pharmaceutically acceptable carrier and/or excipient.

Embodiment 12. A transgenic organism comprising the nucleic acid sequence according to Embodiment 7; or the expression vector according to Embodiment 8.

Embodiment 13. A method of treating or preventing a Respiratory Syncytial Virus (RSV) infection, are at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof:

-   -   a) one or more antibodies or antigen-binding fragments thereof         according to any of Embodiments 1 through 6;     -   b) a nucleic acid sequences according to Embodiment 7;     -   c) an expression vector according to Embodiment 8;     -   d) a host cell according to Embodiment 9; or     -   e) a pharmaceutical composition according Embodiment 10 or         Embodiment 11; such that the RSV infection is treated or         prevented, or the at least on symptom associated with RSV         infection is treated, alleviated, or reduced in severity.

Embodiment 14. A method of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, are at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof:

-   -   a) one or more antibodies or antigen-binding fragments thereof         according to any of Embodiments 1 through 6;     -   b) a nucleic acid sequences according to Embodiment 7;     -   c) an expression vector according to Embodiment 8;     -   d) a host cell according to Embodiment 9; or     -   e) a pharmaceutical composition according Embodiment 10 or         Embodiment 11; such that the RSV infection is treated or         prevented, or the at least on symptom associated with RSV         infection is treated, alleviated, or reduced in severity.

Embodiment 15. The method according to Embodiment 14, wherein the one or more antibodies or antigen-binding fragments thereof comprises Antibody Number 340.

Embodiment 16. The method according to any one of Embodiments 13 through 15, wherein the method further comprises administering to the patient a second therapeutic agent.

Embodiment 17. The method according to Embodiment 16, wherein the second therapeutic agent is selected group consisting of: an antiviral agent; a vaccine specific for RSV, a vaccine specific for influenza virus, or a vaccine specific for metapneumovirus (MPV); an siRNA specific for an RSV antigen or a metapneumovirus (MPV) antigen; a second antibody specific for an RSV antigen or a metapneumovirus (MPV) antigen; an anti-IL4R antibody, an antibody specific for an influenza virus antigen, an anti-RSV-G antibody and a NSAID.

Embodiment 18. A pharmaceutical composition comprising any one or more of the isolated antibodies or antigen-binding fragments thereof of any one of Embodiments 1 through 7 and a pharmaceutically acceptable carrier and/or excipient.

Embodiment 19. The pharmaceutical composition according to Embodiment 18 for use in preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof or suspected of being in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.

Embodiment 20. The pharmaceutical composition according to Embodiment 18 for us in treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.

Embodiment 21. Use of the pharmaceutical composition of Embodiment 18 in the manufacture of a medicament for preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration.

Embodiment 22. Use of the pharmaceutical composition of Embodiment 18 in the manufacture of a medicament for preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use. 

What is claimed is:
 1. An isolated antibody or an antigen-binding fragment thereor that specifically binds to Respiratory Syncytial Virus (RSV) F protein (F), wherein at least one of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and CDRL3 amino acid sequence of the antibody or the antigen-binding fragment thereof is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to at least one the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences as disclosed in Table 6 of an antibody selected from Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; and wherein said antibody or the antigen-binding fragment thereof also has one or more of the following characteristics: a) the antibody or antigen-binding fragment thereof cross-competes with said antibody ar antigen-binding fragment thereof for binding to RSV-F; b) the antibody or antigen-binding fragment thereof displays better binding affinity for the PreF form of RSV-F relative to the PostF form; c) the antibody or antigen-binding fragment thereof displays a clean or low polyreactivity profile; d) the antibody or antigen-binding fragment thereof displays neutralization activity toward RSV subtype A and RSV subtype B in vitro; e) the antibody or antigen-binding fragment thereof displays antigenic site specificity for RSV-F at Site Ø, Site I, Site II, Site III, Site IV, or Site V; f) the antibody or antigen-binding fragment thereof displays antigenic site specificity for RSV-F Site Ø, Site V, or Site III relative to RSV-F Site I, Site II, or Site IV; g) at least a portion of the epitope with which the antibody or antigen-binding fragment thereof interacts comprises the α3 helix and β3/β4 hairpin of PreF; h) the antibody or antigen-binding fragment thereof displays an in vitro neutralization potency (IC₅₀) of between about 0.5 microgram/milliliter (ug/ml) to about 5 ug/ml; between about 0.05 ug/ml to about 0.5 ug/ml; or less than about 0.05 mg/ml; i) the binding affinity and/or epitopic specificity of the antibody or antigen-binding fragment thereof for any one of the RSV-F variants designated as 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG in FIG. 7A is reduced or eliminated relative to the binding affinity and/or epitopic specificity of said antibody or antigen-binding fragment thereof for the RSV-F or RSV-F DS-Cav1; j) the antibody or antigen-binding fragment thereof of displays a cross-neutalization potency (IC₅₀) against human metapneumovirus (HMPV); k) the antibody or antigen-binding fragment thereof does not complete with D25, MPE8, palivisumab, motavizumab, or AM-14; or l) the antibody or antigen-binding fragment thereof displays at least about 2-fold; at least about 3-fold; at least about 4-fold; at least about 5-fold; at least about 6-fold; at least about 7-fold; at least about 8-fold; at least about 9-fold; at least about 10-fold; at least about 15-fold; at least about 20-fold; at least about 25-fold; at least about 30-fold; at least about 35-fold; at least about 40-fold; at least about 50-fold; at least about 55-fold; at least about 60-fold; at least about 70-fold; at least about 80-fold; at least about 90-fold; at least about 100-fold; greater than about 100-fold; and folds in between any of the foregoing; greater neutralization potency (IC50) than D25 and/or palivizumab.
 2. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof comprises: at least two; at least three; at least 4; at least 5; at least 6; at least 7; at least 8; at least 9; at least 10; at least 11; or at least 12; of characteristics a) through l).
 3. The isolated antibody or antigen-binding fragment thereof of claim 1 or 2, wherein the antibody or antigen-binding fragment thereof comprises: a) the CDRH3 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; b) the CDRH2 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; c) the CDRH1 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; d) the CDRL3 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; e) the CDRL2 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; f) the CDRL1 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; or g) any combination of two or more of a), b), c), d), e), and f).
 4. The isolated antibody or antigen-binding fragment thereof of any one of claims 1 through 3, wherein the antibody or antigen-binding fragment thereof comprises: a) a heavy chain (HC) amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; and/or b) a light chain (LC) amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table
 6. 5. The isolated antibody or antigen-binding fragment thereof of any one of claims 1 through 4, wherein the antibody is selected from the group consisting antibodies that are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to any one of the antibodies designated as Antibody Number 232 through Antibody Number 372 as disclosed in Table
 6. 6. The isolated antibody or antigen-binding fragment thereof of any one of claims 1 through 5, wherein the antibody is selected from the group consisting of the antibodies designated as Antibody 232 through Antibody Number 372 as disclosed in Table
 6. 7. An isolated nucleic acid sequence encoding an antibody or antigen-binding fragment thereof according to any one of claims 1 through
 6. 8. An expression vector comprising the isolated nucleic acid sequence according to claim
 7. 9. A host cell transfected, transformed, or transduced with the nucleic acid sequence according to claim 7 or the expression vector according to claim
 8. 10. A pharmaceutical composition comprising: one or more of the isolated antibodies or antigen-binding fragments thereof according to any one of claims 1 through 6; and a pharmaceutically acceptable carrier and/or excipient.
 11. A pharmaceutical composition comprising: one or more nucleic acid sequences according to claim 7; or one or more the expression vectors according to claim 8; and a pharmaceutically acceptable carrier and/or excipient.
 12. A transgenic organism comprising the nucleic acid sequence according to claim 7; or the expression vector according to claim
 8. 13. A method of treating or preventing a Respiratory Syncytial Virus (RSV) infection, are at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof: a) one or more antibodies or antigen-binding fragments thereof according to any of claims 1 through 6; b) a nucleic acid sequences according to claim 7; c) an expression vector according to claim 8; d) a host cell according to claim 9; or e) a pharmaceutical composition according claim 10 or claim 11; such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.
 14. A method of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, are at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof: a) one or more antibodies or antigen-binding fragments thereof according to any of claims 1 through 6; b) a nucleic acid sequences according to claim 7; c) an expression vector according to claim 8; d) a host cell according to claim 9; or e) a pharmaceutical composition according claim 10 or claim 11; such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.
 15. The method according to claim 14, wherein the one or more antibodies or antigen-binding fragments thereof comprises Antibody Number
 340. 16. The method according to any one of claims 13 through 15, wherein the method further comprises administering to the patient a second therapeutic agent.
 17. The method according to claim 16, wherein the second therapeutic agent is selected group consisting of: an antiviral agent; a vaccine specific for RSV, a vaccine specific for influenza virus, or a vaccine specific for metapneumovirus (MPV); an siRNA specific for an RSV antigen or a metapneumovirus (MPV) antigen; a second antibody specific for an RSV antigen or a metapneumovirus (MPV) antigen; an anti-IL4R antibody, an antibody specific for an influenza virus antigen, an anti-RSV-G antibody and a NSAID.
 18. A pharmaceutical composition comprising any one or more of the isolated antibodies or antigen-binding fragments thereof of any one of claims 1 through 7 and a pharmaceutically acceptable carrier and/or excipient.
 19. The pharmaceutical composition according to claim 18 for use in preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof or suspected of being in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.
 20. The pharmaceutical composition according to claim 18 for us in treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, ar at least one symptom associated with said RSV infection or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.
 21. Use of the pharmaceutical composition of claim 18 in the manufacture of a medicament for preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration.
 22. Use of the pharmaceutical composition of claim 18 in the manufacture of a medicament for preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, are at least one symptom associated with said RSV infection or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use. 